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1. Overview
2. Current proteasome inhibitors:
novel chemical entities created
specifically for inhibiting the
proteasome
3. Combination therapy: known
or novel compounds used in
combination with other
known drugs for proteasome
inhibition and synergy of
therapeutic effect
4. Expert opinion
Review
Proteasome inhibitor patents(2010 -- present)Rainer Metcalf, Latanya M Scott, Kenyon G Daniel & Q Ping Dou†
†Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
Introduction: Over the past 3 years, numerous patents and patent applica-
tions have been submitted and published involving compounds designed to
inhibit the proteasome. Proteasome inhibition has been of great interest in
cancer research since disruption of proteolysis leads to a significant buildup
of cytotoxic proteins and activation of apoptotic pathways, particularly in
rapidly proliferating cells. The current standards in proteasome inhibition
are the only FDA-approved inhibitors, bortezomib and carfilzomib. Although
these drugs are quite effective in treating multiple myeloma and other blood
tumors, there are shortcomings, including toxicities and resistance. Most of
the current patents attempt to improve on existing compounds, by increasing
bioavailability and selectivity, while attempting to reduce toxicity. A general
categorization of similar compounds was employed to evaluate and compare
drug design strategies.
Areas covered: This review focuses on novel compounds and subsequent
analogs developed for proteasome inhibition, used in preventing and
treating human cancers. A comprehensive description and categorization of
patents related to each type of compound and its derivatives, as well as their
uses and efficacies as anticancer agents is included. A review of combination
therapy patents has also been included.
Expert opinion: Although there are many diverse chemical scaffolds being
published, there are few patented proteasome inhibitors whose method of
inhibition is genuinely novel. Most patents utilize a destructive chemical war-
head to attack the catalytic threonine residue of the proteasome active sites.
Few patents try to depart from this, emphasizing the need for developing
new mechanisms of action and specific targeting.
Keywords: anticancer therapy, bortezomib, carfilzomib, clinical trials, drug discovery, patents,
polyphenols, proteasome inhibitors
Expert Opin. Ther. Patents [Early Online]
1. Overview
Protein turnover is an essential part of amino acid metabolism in which cells con-stantly synthesize and degrade proteins. The rate of expression and degradation ofproteins is critical for the proper regulation of metabolic pathways. The proteasomeis a nearly universal cellular component and integral for this fundamental biologicalprocess [1,2].
The 26S mammalian proteasome is a massive 2400 kDa molecule comprising a20S core particle (CP) and one or two 19S 18-subunit regulatory particle(RP) [3]. The RP, or PA700 cap, also incorporates specific recognition sites to whichubiquitin chains can bind [4]. The CP is a 700 kDa, barrel-shaped structure com-posed of four six-subunit rings [5]. The a subunits of the outer rings are largelystructural in function and appear to regulate the formation and stabilization ofeither the 26S proteasome or 19S immunoproteasome [6]. Proteolysis occurs atthe six protease active sites of the inner ring b subunits oriented toward the lumen
10.1517/13543776.2014.877444 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 1All rights reserved: reproduction in whole or in part not permitted
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of the proteasome [3]. These active sites comprise a catalyticregion and multiple recognition regions [7]. The catalyticregions are similar and incorporate a catalytic threonine 1(Thr 1) residue to execute the hydrolysis of the protein [3].Discretionary binding of specific residue sequences is accom-plished by the recognition regions of the active sites [8]. Thesesites are designated as the b1/PRE3peptidylglutamyl peptidecaspase-like recognition site (PGPH), the b2/PUP1 trypsin-like recognition site (T-L) and the b5/PRE2 chymotrypsin-like recognition site (CT-L) [9]. Other structural variants ofthe proteasome have been discovered and they exhibit slightlyaltered functions of the b subunits and regulatory caps.The immunoproteasome consists of smaller 11S RPs and amodified 20S CP containing ib1, ib2 and ib5 subunits andstructural isoforms of the constitutive b1, b2 and b5 subunits,respectively [10]. The thymoproteasome is another proteaso-mal polymorphism more recently elucidated, which incorpo-rates the ib1 and ib2 immunoproteasome subunits butintegrates a constitutively differing tb5 subunit [11]. Disrup-tion of proteolysis can lead to significant buildup of cytotoxicproteins and activation of apoptotic pathways, particularly inrapidly proliferating cells [12].For this reason, proteasome inhibition has been of great
interest in cancer research [13]. Further studies into the useof proteasome inhibitors on oncogenic cell lines have revealedthat they may prevent angiogenesis and metastasis andincrease susceptibility to apoptosis, while quiescent cells maybe preserved to some extent [14]. Possible therapies for otherdiseases and disorders, such as neurodegenerative disorders [15],cardiac disease [16,17] and organ transplant rejection [18], arebeing researched.The patent search strategy was carried out with focus on
patents or applications from the past 3 years that cover newchemical entities, or new methods of using natural products,known chemical entities, or any combinations of the afore-mentioned as inhibitors of proteasome activity. Additionally,the scope of utility of these patents was not limited to onlycover cancer therapy but included patents that teach protea-some inhibition as a method of treating other diseases, suchas immunological disorders or viral infections. The search
was initiated broadly to capture the most patents and applica-tions filed between 1 January 2010 and 30 September 2013,using the Delphion patent database from Thomson Reuters.This search focused on finding representative classes ofnew chemical entities being claimed as novel proteasomeinhibitors.
2. Current proteasome inhibitors: novelchemical entities created specifically forinhibiting the proteasome
Proteasome inhibitors can be categorized into several differentchemical classifications. A recent review article written by ourgroup outlined a generalized list of current proteasome inhibi-tors based on chemical structure and reaction mechanism [19].Many patents tend to circulate around existing structures,seeking to improve potency and selectivity. These analogs pos-sess a similar pharmacophore comprising two key elements: apeptide portion that selectively binds to the recognition bind-ing pocket of the proteasome with high affinity and a chemicalmoiety specifically designed to interact with the catalytic Thr1 residue to irreversibly inhibit protease activity [20]. Commonfunctional groups that are exploited to react with the catalyticThr 1 residue are aldehydes, vinyl sulfones, boronates, epoxy-ketones and b-lactones.
2.1 Boron-containing compoundsBoron-containing inhibitors capitalize on highly reactiveboron-containing ‘warheads’ to create a covalent ligature toa protein. Therefore, these types of molecules are generallynoncompetitive and extremely potent, with IC50 values oftenin the nanomolar and picomolar range. One of the mostwell-known proteasome inhibitors, bortezomib (Figure 1-1),is of this type, utilizing a boronic acid moiety to perform anucleophilic attack on the CT-L catalytic Thr 1 residue.This mechanism is a frequently adopted design strategy withattempts geared mainly to decrease side effects. Althoughbortezomib is a potent and effective proteasome inhibitor, ithas been found to have several and often severe side effects,including fatigue, nausea, sensory neuropathy and adversecardiovascular effects [21,22]. Additionally, the developmentof bortezomib resistance in patients and preliminary studiesshowing limited effect on solid tumors are beinginvestigated [23-26].
Li et al. developed multiple compounds directed primarilyat alleviating the side effects of bortezomib. The most activecompound, 6f (Figure 1-2), displayed a CT-L IC50 of0.079 ± 0.011 µM in biochemical assays, as well as an IC50
of 3.630 ± 1.669 µM in the PGPH-active site [27]. It alsoexhibited greater efficacy in cellular assays than bortezomibat 0.5 µM across multiple cell lines: HL-60 human leukemiawith 87% inhibition, BGC-823 human gastric cancer with95% inhibition, bel-7402 human hepatocarcinoma with94% inhibition and Kb human nasopharyngeal carcinoma
Article highlights.
. Proteasome inhibition remains an effective technique incancer therapy.
. A few recent proteasome inhibitor patents are genuinelynovel in their method of inhibition.
. Most patents attempt to utilize epigallocatechin gallateor a peptidomimetic moiety coupled with a chemicallyreactive warhead.
. None of the currently published compounds appear tohave the optimal combination of potency, toxicityand bioavailability.
This box summarizes key points contained in the article.
R. Metcalf et al.
2 Expert Opin. Ther. Patents (2014) 24(4)
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with 96% inhibition. Further, in vivo testing showed a 55%tumor inhibition [27]. Unfortunately, a 63% survival rateresonated as on par with the toxicity of bortezomib [27].Compound 6g (Figure 1-3), in contrast, presented an efficacycomparable to bortezomib in biochemical and cellular assays,but with a 100% survival rate in rat models [27].
An interesting approach to the use of a chemical warheadby utilizing a type of protecting group on the warhead canbe illustrated in the patent by Bernardini et al. [28]. This pro-tecting group serves two purposes: one being that it masks thepolarity of the highly polar boronic acid moiety, therebyincreasing bioavailability, and two, it attempts to decrease
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Figure 1. Boron-containing compounds are shown.
Proteasome inhibitor patents (2010 -- present)
Expert Opin. Ther. Patents (2014) 24 (4) 3
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the reactivity of the warhead until binding, conceivably reduc-ing off-target effects. The patent outlined a large array ofexample compounds, but the general structure shownin Figure 1-4 characterizes the basic form of the protectinggroup on the boronic acid warhead. The group did a simplehigh-throughput screening to ascertain IC50 and EC50 valuesfor each compound [28]. Compounds with the general formin Figure 1-4 displayed biochemical assay IC50 valuesof < 10 nM and EC50 values of < 200 nM in Molt 4 cells [28].The compound shown in Figure 1-5 is a specific example,representative of the general form (Figure 1-4).Other recent patents on bortezomib analogs include
compounds I-20 (Figure 1-6) [29], with a reported IC50
of < 50 nM and a list of compounds with the general structureshown in Figure 1-7 by Shenk et al. [30]. Another patent ofnote is on distinct formulations for stabilizing bortezomib ina liquid form suitable for injection [31]. While this patentmay not seek claim for a specific compound, it does showalternative patent strategies in the realm of drug design.
2.2 EpoxyketonesEpoxyketones garnered significant interest after the introduc-tion of carfilzomib (Figure 2-1) as a safer, more specific andmore effective proteasome inhibitor than bortezomib [32].Carfilzomib was designed as an analog to epoxomicin basedon its in vivo antitumor activity [33]. The epoxyketone
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Figure 2. Epoxyketone-containing compounds are shown.
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4 Expert Opin. Ther. Patents (2014) 24(4)
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pharmacophore is the main chemical moiety developed toattack the CT-L catalytic Thr 1 residue by forming a dualcovalent morpholino adduct [34].
Compound 1 (Figure 2-2) was patented by Kirk and Jiangand showed that dosages of 30 -- 40 mg/kg reduce the numberof visible metastatic tumors in lungs by ~ 50% [35].Shenk et al. applied for a patent on compound 14 (Figure 2-3) specifically as a potential treatment for rheumatoid arthri-tis. Their work showed that dosages at 6 mg/kg reducedarthritis symptom severity in rat models by 50% [30,36].Smyth et al. published multiple patents focusing solely onthe structure and synthesis of compounds that emphasize adiversity of peptide mimetics employing an epoxyketonewarhead [37-39]. The general structure is shown in Figure 2-4.
Most proteasome inhibitors target the hydrophobic CT-Lsite since the majority of pharmaceutically viable com-pounds must be relatively hydrophobic themselves. Thisleaves the other sites severely underresearched as targets.Kisselev et al. developed compounds with the intent of spe-cifically inhibiting the T-L active site [40]. The compoundNC-022 (Figure 2-5) displayed preferential binding to theT-L site with an IC50 of 38 nM [40]. Other analogs por-trayed similar potencies; however, NC-022 was the mostcell-permeable compound and, thus, held the greater poten-tial as an applicable therapeutic [40]. The authors also foundthat vinyl sulfones tended to be more potent and moreselective for T-L than epoxyketones with same sequenceand showed that T-L inhibition sensitizes cells to CT-Linhibitors, leading to possible combination therapies men-tioned in later sections [40].
Despite the success of carfilzomib, epoxyketones capitalizeon the same basic mechanism as bortezomib and sharemany of the common patient inconveniences and side effects.Although Carfilzomib demonstrated a 22.9% overall responserate in clinical studies and showed reduced incidence ofperipheral neuropathies compared to bortezomib [9,41], carfil-zomib still presented some side effects including pneumonia,acute renal failure, pyrexia, congestive heart failure, cytopenia,fatigue, nausea and dyspnea [32,41]. Continued research andimprovements on this family of compounds are necessary toyield more safe and effective therapeutic options.
2.3 Green tea-derived polyphenolic compoundsEpigallocatechin gallate (EGCG) (Figure 3-1) has gained con-siderable interest in cancer treatment due to evidence of itsability to inhibit growth of several types of cancers [42-49].Other studies have also shown EGCG to have certain selectivebinding to the proteasome, making it a potential model fordesigning novel proteasome inhibitors [50]. EGCG belongsto a class of natural products known as flavonoids, commonlyfound in green tea and other edible plants [51].
The EGCG analogs, compounds 5 and 7 (Figure 3-2 and 3-
3, respectively), studied by Chan et al. show promise in thetreatment of multiple myeloma (MM) ARP cells within vitro tests displaying 70% growth inhibition at 50 µM for
compound 5 and 95% growth inhibition for compound7 at the same concentration [52]. Another patent by the sameauthor endeavored to increase the bioavailability of EGCGby increasing the hydrophobicity of the compounds anddecreasing the rate of metabolism by introducing protectinggroups [53]. By acetylating all of the hydroxyl groups onEGCG, the authors were able to create a prodrug (compound 1,Figure 3-4) that exhibited slower metabolic degradation andgreater cell permeability, while retaining the potency ofEGCG [53].
Patents for synthetic polyphenolic compounds developedby our group show interesting improvements in efficacy bychanging the stereochemistry of natural products. By switch-ing the chirality of the natural compounds, (--)-EGCG (Fig-ure 3-1) and (--)-GCG (Figure 3-5), to the opposite planepolarized forms, (+)-EGCG (Figure 3-6) and (+)-GCG (Fig-ure 3-7), the authors were able to substantially increasepotency from IC50 values of 205 nM for (--)-EGCG to170 nM for (+)-EGCG, and 610 nM for (--)-GCG to270 nM for (+)-GCG [54].
Unmodified flavonoids are generally weak inhibitors, withcommon IC50 values in the range of many micromolars.However this property, coupled with their low toxicity andantioxidant activities, allows flavonoid analogs to fulfill aunique niche as low-risk agents that could be incorporatedinto diet as part of a preventative strategy for disease.
2.4 Metal complexesMetal complexes using gold [55,56], nickel [57,58], zinc [57,58]
and to a greater degree copper [59-63], have received significantattention due to their unique pharmacophore. Coppercomplexes have been viewed with particular promise aspotential proteasome inhibitors, in addition to a nascentstrategy in cancer therapy, after studies showed that cancercells accumulate more copper than healthy cells [59-63].8--hydroxyquinoline (8OHQ) (Figure 4-1) has been wellknown as a monoprotic bidentate chelating agent for sometime [64], although its potential as a proteasome inhibitorwas only recently elucidated when our group found that the8OHQ analog, clioquinol (Figure 4-2), inhibited the CT-Lactivity of the proteasome, blocked proliferation and inducedapoptosis in breast cancer cells, while remaining nontoxic tononcancerous breast cells [60]. Since then, there have been sev-eral novel inhibitor designs incorporating the basic 8OHQstructure.
Recent analogs, 5-amino-8-hydroxyquinoline (5AHQ)(Figure 4-3), of 8OHQ by Schimmer include an additionalamino group and has similar IC50 values as 8OHQ [65].In vivo assays of 5AHQ against human leukemia displayedmodest IC50 values of 3.7 ± 0.3 µM. Sheshbaradaranexploited the preformed gallium metal complex, tris(8-quinolinolato)gallium(III) (Figure 4-4), at 2.5 -- 5 µM incombination with 5 nM concentration of bortezomib toshow a near 100% growth inhibition of lung cancertissue [66].
Proteasome inhibitor patents (2010 -- present)
Expert Opin. Ther. Patents (2014) 24 (4) 5
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Figure 3. Green tea-derived polyphenolic compounds are shown.
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2.5 Salinosporamide analogsThe marine natural product, salinosporamide A (Figure 5-1),has recently received considerable notice mainly due to itsremarkable potency as a proteasome inhibitor with IC50 valuesoften reaching the low picomolar range. The g-lactam--b-lactone bicyclic core of salinosporamide A is the fundamentalstructure and also functions as a proteasome inhibitor bycovalently modifying active site threonine residues [67-69].
The replacement of the chlorine group on salinosporamideA to a hydroxyl group (Figure 5-2) led to a substantial decreasein cytotoxicity, 38 ± 4 µM compared to 9.8 ± 3 nM, whileretaining potency, CT-L IC50 of 14 ± 1.5 nM compared to2.5 ± 1.2 nM, and increasing selectivity for the CT-L activesite [70]. Various compounds with the general structurein Figure 5-3 were patented by Ling et al. [71]. The patentincluded a method for synthesizing the natural product andthe structures of any intermediates formed in the process.The authors also compared the differences in inhibitionbetween production through fermentation and syntheticmanufacturing [71]. The synthetic form, being more pure,exhibited a slightly better CT-L IC50 of 3.2 nM and 96%inhibition of the 20S proteasome in RPMI 8826 cells at10 nM concentrations [71].
Although the natural form of salinosporamide A cannot bepatented, Fenical et al. have applied for a patent on multiplestereoisoforms of salinosporamide [72] and early clinical trialsof the natural compound, clinically named marizomib,
indicate a strong potential for a viable treatment of variouscancers [73-76].
Natural products isolated from marine organisms haveserved as an exceptional source for unique lead compoundsin drug design [77,78]; therefore, it is not surprising to see arepresentative of this class of compounds showing potentialas a prime archetype for a new class of novel proteasomeinhibitors. Salinosporamide will likely continue to be of inter-est to researchers and a robust pharmacophore in future drugdesign strategies.
2.6 Unique chemical designsWhereas many patents utilize previously discovered structuresas a pharmacophore for developing novel compounds, therehave been some recent publications employing entirely originalstructures. The apparent majority of effective proteasomeinhibitors are noncompetitive and make use of some sort of‘warhead’ to covalently modify the active site threonineresidues. Competitive proteasome inhibitors rarely achieveactivities lower than several micromolars. However,Lawrence et al. discovered an interesting compound, PI-1833(Figure 6-1), reporting an IC50 of 630 ± 350 nM. The groupalso tested multiple analogs with some (PI-1840, Figure 6-2)achieving reported values of 32 ± 0.15 nM, alluding to thepossibility of having found the first competitive proteasomeinhibitors comparable to bortezomib [79]. The same groupalso discovered another unique compound, HLM-008182 (Fig-ure 6-3), with a reported IC50 of 650 ± 40 nM [80].
Another innovative patent by Bachovchin et al. [81] capital-izes on the overexpression of fibroblast activation protein(FAP) in stromal fibroblasts of epithelial cancers [82]. FAPbinds to a specific peptide sequence attached to a cytotoxicmoiety; Figure 6-4 is an example of one such peptide sequence.The enzyme cleaves the compound to release the active moi-ety only when present in cells with sufficient expression ofFAP [81]. While the active moiety may not necessarily be aproteasome inhibitor, the patent includes many of theaforementioned warheads utilized as the active group, R,in Figure 6-5. The patent focuses primarily on the mechanismof FAP-activated compounds, allotting to the possible incor-poration of any cytotoxic moiety for the treatment of epithe-lial carcinomas. Although the novelty of this patent is nottechnically in proteasome inhibition, its inclusion in thisreview is significant due to the patent’s unique attempt tospecifically deliver a proteasome inhibitor to certain cancercells.
Even though these compounds have only recently beendiscovered and are a long way from the clinical use, furtherinvestigation and design improvement will no doubt yieldcompounds with considerable potential as therapeutic agents.In order to surmount the obstacles faced by these promisingleads, an ongoing research effort is essential to understandhow these compounds achieve such high potencies and possi-bly elucidate new pharmacophores for effective competitiveproteasome inhibition.
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Figure 4. Metal complexes are shown.
Proteasome inhibitor patents (2010 -- present)
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3. Combination therapy: known or novelcompounds used in combination with otherknown drugs for proteasome inhibition andsynergy of therapeutic effect
Biochemical pathways in cells are seldom isolated. Fully inhib-iting one enzyme may deplete a specific product or stress thecell but will rarely shutdown an entire pathway in vivo. Otherintersecting metabolic routes can assist in replenishing prod-ucts and may even completely overcome the induced‘roadblock’ [83-87]. Additionally, being tiny crucibles of strainedgenetic evolution, cancerous tissue is constantly battling to sur-vive utilizing the sheer brute force of mathematical chance.Cancer cells require only a single chance adaption to a drugto gain resistance [88,89]. The method of combination therapyseeks to address these problems, since a tumor cell is far lesslikely to gain resistance to multiple drugs before dying. Fur-ther, different drugs can act to inhibit alternate pathways orsensitize the cell to other drugs, leading to synergistic effects.Fertig et al. designed an anti-CD20 antibody, a humanized
B-Ly1 antibody, to be used alone and in combination withseveral proteasome inhibitors, including Bortezomib,
rituximab and cyclophosphamide [90]. Mice xenographs ofSU-DHL-4 non-Hodgkin’s lymphoma cells showed 87%inhibition with the antibody alone [90]. Although this therapywas effective by itself, combination therapy with bortezomibresulted in lymphoma regression and complete tumor remis-sion with no regrowth in four of nine animals [90]. Forstercapitalized on patenting the usage of several types of glucocor-ticoids in conjunction with proteasome inhibitors to mitigatebrain or spinal cord damage following an ischemic event [91].By stabilizing the blood--brain barrier with glucocorticoids todiminish tissue edema and administering a proteasome inhib-itor in an attempt to prevent the degradation of the inhibitoryprotein IkB-a, which downregulates NF-kB, a necrosis fac-tor, neuronal death can be abated long enough until the tissuecan be reperfused or oxygenated [91].
Delanzomib (Figure 1-8) is another compound discoveredsome time ago with a similar pharmacophore as bortezo-mib [92]. This drug has recently gone through Phase I clinicaltrials for treatment of MM and advanced solid tumors [93].Delanzomib does appear to alleviate some of the peripheralneuropathy seen in bortezomib treatments but it still suffersfrom many of the same side effects, albeit to a lesser degree [93].Although delanzomib is currently being researched as a possi-ble cancer treatment, Ruggeri and Seavey have already sub-mitted a patent for its use as a potential treatment oflupus [94]. Studies have found that the administration ofdelanzomib improved survival and reduced lupus nephritisin MRL/lpr and BWF1 mouse models [95].
Some patents mentioned previously that contained addi-tional outlines for possible combination therapies are5AHQ (Figure 4-3), which when combined with 10 nM con-centration of bortezomib exhibited a synergistic effect acrossmultiple cell lines, including MM, leukemia and solidtumors [65].
The T-L inhibitor, NC-022 (Figure 2-4), developed byKisselev et al. exhibited a strong synergistic effect with otherCT-L inhibitors [40]. When combined with 33 nM bortezo-mib, an 81 ± 19% growth inhibition of MM cells comparedto 47 ± 13% with bortezomib alone at the same concentrationwas noticed [40]. The authors also tested the compound with aminor 3.7 nM concentration of carfilzomib to achieve a 64 ±15% growth inhibition in MM cells, a substantial contrast tothe near negligible 1 ± 9% growth inhibition with the sameconcentration of carfilzomib alone [40].
A patent can be obtained solely on a method of using acertain chemical entity. However, if there exists another pat-ent on the structure of that chemical entity, the applicant ofthe method--of-use patent would need the permission of theother patent holder to be able to legally practice themethod-of-use invention. When this occurs, the other patentis said to ‘dominate’ the first patent. With this in mind, pat-ents that solely cover the methods of using a combination ofchemical entities tend to be lower on patent hierarchy.Although easily overshadowed, the value of a pure methodof use patent becomes apparent if no one can obtain a patent
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Figure 5. Salinosporamide analogs are shown.
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8 Expert Opin. Ther. Patents (2014) 24(4)
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for the chemical entity itself. This can manifest when a chem-ical entity is found to occur in nature. Although they can bediscovered or isolated, natural products themselves are notpatentable subject material. The caveat lies in that distinctmethods of using natural products are patentable subjectmaterial. In this case, there is more of a level playing field,where a chemical entity structure patent cannot dominate amethod of use patent.
4. Expert opinion
In general, a person has a right to patent an invention in USA
as long as the invention is not an abstract idea, a law of nature,
or naturally occurring, and is useful, novel and non-obvious
to one of ordinary skill in the art. What that equates to in lay-
man’s terms is that an invention must be conceived of and
made by humans, must have some useful purpose, must
have never been known or publicly described before seeking
a patent and is not an obvious invention to one with general
and basic skill and knowledge in the field. Many factors
come into play when deciding to file a patent application
for a particular invention, with the potential value of the
invention’s utility often being a major factor. In the pharma-
ceutical field, one can think of a chemical entity’s value as
hierarchical; patents on the structure of new chemical entities
are often considered the most valuable, because they carry the
most weight in terms of excluding others from making or
practicing a patented invention. No one else can use that
chemical entity for any purpose without the holder’s permis-
sion throughout the duration of the patent term, because
they own the rights to make and use the structural matter.
The fact that most of the patents and applications that we
uncovered in our searches include, in some way, claiming
new chemical entities themselves is reflective of the prime
value of this type of patent position.
There are over 10 structurally distinct classes of proteasomeinhibitors, signifying a rich diversity of chemical space. This isimportant for the novelty of a patent; however, nearly all ofthe aforementioned chemical entities can be categorized intotwo general types based on the mechanism of action: a chem-ical warhead affixed to peptide for recognition or copyingEGCG to make a competitive inhibitor. Most patents makeuse of a chemical warhead and a peptidomimetic moiety toselectively bind to the CT-L active site, ignoring the other
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Figure 6. Unique chemical designs are shown.
Proteasome inhibitor patents (2010 -- present)
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two sites completely, and covalently attack the catalytic threo-nine. Covalent inhibitors are chemically reactive, tending toproduce toxic metabolites and have severe off-target reactions.As a result, competitive inhibitors may be more desirablewhen tissue targeting is not considered, since current compet-itive inhibitors tend to have less severe side effects. This trendis not absolute, however, as the mechanisms of competitiveinhibitors are often less understood compared to noncompet-itive inhibitors, possess poorer potency and many have a sim-ilar number of off-target interactions. Based on the patentlandscape, research into competitive proteasome inhibitors islimited and innovation in this field is also something to bedesired. Repeatedly, others attempting to make a true com-petitive inhibitor synthesize EGCG analogs based on theinformation of EGCG--proteasome b5 interactions. Thebioavailability of EGCG and analogs poses pharmacologicalchallenges but provides a unique role in the realm of preven-tion vis-a-vis diet for this class of compounds. This argumentof novelty is semantic but it does attempt to exposeentrenched methods of drug design. Although the practiceof improving a previously discovered pharmacophore doesyield results, it is essential to focus on developing new mech-anisms of action and, more importantly, specific targeting.Specific targeting of cancer cells has remained an elusive
goal. Due to this, most drugs attempt to take advantage ofthe fact that oncogenic tissues tend to be more susceptibleto cytotoxic effects than normal healthy tissue. Therefore,introducing compounds that cause global toxicity should, the-oretically, kill the cancer before killing the patient. This con-cept has yielded less than desirable results and has often led tothe question of which is worse, the cure or the disease. Cur-rent attempts at proteasome inhibitors are no different.Whereas global inhibition of the proteasome has been shownto have limited toxic effects on healthy tissue, this does notrender healthy tissue immune to proteasome inhibition orresistant to other off-target effects that may arise due to thepresence of a chemically reactive warhead. Further, bortezo-mib might have some off-targets, which are associated withthe emergence of peripheral neuropathy. There has been evi-dence in clinical trials that bortezomib may have otherproteasome-independent mechanisms of action in additionto proteasome inhibition [96-103]. These articles show alternatepathways being activated or downregulated, leading to cyto-toxicity and possible causes of adverse drug effects. Analysisof gene expression profiles and single nucleotide polymor-phisms (SNPs) of myeloma plasma cells and peripheral bloodsamples have identified genes and SNPs associated with mito-chondrial dysfunction and DNA repair [98]. Whereas these canbe expressed through proteasomal pathways, interference withribosome function, essential DNA damage pathways and dys-regulation of many other metabolic processes can be attrib-uted to other off-target interactions [104,105]. Previous studieshave indicated that bortezomib-induced neurodegenerationin vitro occurs exclusively by way of a proteasome-independent mechanism and that bortezomib inhibits several
non-proteasomal peptidase targets in vitro and in vivo [106,107].Another gene expression profiling study found that the cyto-toxic effects of bortezomib were not p27-dependent and con-firmed that bortezomib increases the expression of genesassociated with endoplasmic reticulum stress, whereas protea-some subunit knockdown alone does not [108]. Consistently,carfizolmib, which is more specific to inhibit the CT activitythan bortezomib, has been shown to have decreased levels ofperipheral neuropathy in myeloma patients, compared tobortezomib.
Along this line, any compound utilizing a chemical war-head will suffer from these off-target interactions to someextent. Although a peptide mimic attached to the chemicalwarhead increases selectivity, the reactivity of these warheadsis independent of binding with intended targets and it is likelythat the warhead will react with other targets in similar chem-ical environments. If a drug can properly protect the warheaduntil binding, global inhibition is still a viable strategy so longas the side effects can be suitably mitigated. On the otherhand, toxic compounds can be utilized with great efficacy ifthey can be delivered exclusively to cancer cells. Either way,any truly effective cancer therapy must involve a solution forspecific targeting and/or exclusive delivery to cancer tissue.
Over the past decade, proteasome inhibition has emergedas an effective method for treating MM and other blood can-cers, in which bortezomib plays an important role. However,some limitations were identified in bortezolmib’s use.A prominent factor is adduced from the severe side effectsthat relegate clinical studies of bortezomib to late stage, termi-nal cancer patients. In late-stage cancer, treatments utilizingproteasome inhibition are ineffective, since apoptotic machin-ery in the cancer cell is usually dismantled. Carfilzomib hasimproved specificity and decreased peripheral neuropathy. Itwill remain to be further investigated if carfilzomib canassuage some criticisms of proteasome inhibition as a cancertherapy in practical application. Hopefully, researchers canlearn from the difficulties of bortezomib and carfilzomiband develop other clinical candidates and therapeutics thatcan attain the perfect balance of potency, toxicity andbioavailability in the future.
Acknowledgments
The authors would like to thank N Shakfeh for her assistancein drawing the chemical structures. Rainer Metcalf andLatanya Scott have contributed equally to the manuscript.
Declaration of interest
This work was supported by the Moffitt Cancer CenterResearch Institute, the University of South Florida College ofArts and Sciences, Karmanos Cancer Institute and Wayne StateUniversity. The authors declare no conflict of interest and havereceived no payment in preparation of this manuscript.
R. Metcalf et al.
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BibliographyPapers of special note have been highlighted as
either of interest (�) or of considerable interest(��) to readers.
1. Rubin DM, Finley D. The proteasome:
a protein-degrading organelle? Curr Biol
1995;5:854-4
2. Baumeister W, Walz J, Proteolysis C.
The proteasome: compartmentalizing
protease. Cell 1998;92:367-80
3. Groll M, Ditzel L, Lowe J, et al.
Structure of 20S proteasome from yeast
at 2.4 A resolution. Nature
1997;386(6624):463-71
4. Elsasser S, Gali RR, Schwickart M, et al.
Proteasome subunit Rpn1 binds
ubiquitin-like protein domains.
Nat Cell Biol 2002;4:725-30
5. Pickart CM, Cohen RE. Proteasomes
and their kin: proteases in the machine
age. Nat Rev Mol Cell Biol
2004;5:177-87
6. Bose S, Stratford F, Broadfoot K, et al.
Phosphorylation of 20S proteasome alpha
subunit C8 (alpha7) stabilizes the 26S
proteasome and plays a role in the
regulation of proteasome complexes by
gamma-interferon. Biochem J
2004;378:177-84
7. Borissenko L, Groll M. 20S proteasome
and its inhibitors: crystallographic
knowledge for drug development.
Chem Inform 2007;38:687-717
8. Tsvetkov L, Nanjundan M, Domino M,
et al. The ubiquitin-proteasome system
and assays to determine responses to
inhibitors. Expert Opin Drug Discov
2010;5:1221-36
9. Kisselev AF, van der Linden WA,
Overkleeft HS. Proteasome inhibitors:
an expanding army attacking a unique
target. Chem Biol 2012;19:99-115
10. Kloetzel PM, Ossendorp F. Proteasome
and peptidase function in MHC-class-I-
mediated antigen presentation.
Curr Opin Immunol 2004;16:76-81
11. Murata S, Takahama Y, Tanaka K.
Thymoproteasome: probable role in
generating positively selecting peptides.
Curr Opin Immunol 2008;20:192-6
12. An W, Hwang S, Trepel J, et al.
Protease inhibitor-induced apoptosis:
accumulation of wt p53, p21WAF1/
CIP1, and induction of apoptosis are
independent markers of proteasome
inhibition. Leukemia 2000;14:1276
13. Rajkumar SV, Richardson PG,
Hideshima T, et al. Proteasome
inhibition as a novel therapeutic target in
human cancer. J Clin Oncol
2005;23:630-9
14. Almond J, Cohen G. The proteasome:
a novel target for cancer chemotherapy.
Leukemia 2002;16:433
15. Paul S. Dysfunction of the
ubiquitin--proteasome system in multiple
disease conditions: therapeutic
approaches. Bioessays 2008;30:1172-84
16. Willis MS, Townley-Tilson WD,
Kang EY, et al. Sent to destroy: the
ubiquitin proteasome system regulates
cell signaling and protein quality control
in cardiovascular development and
disease. Circ Res 2010;106:463-78
17. Yu X, Kem DC. Proteasome inhibition
during myocardial infarction.
Cardiovasc Res 2010;85:312-20
18. Flechner SM, Fatica R, Askar M, et al.
The role of proteasome inhibition with
bortezomib in the treatment of antibody-
mediated rejection after kidney-only or
kidney-combined organ transplantation.
Transplantation 2010;90:1486-92
19. Pevzner Y, Metcalf R, Kantor M, et al.
Recent advances in proteasome inhibitor
discovery. Expert Opin Drug Discov
2013;8:537-68
20. Kisselev AF, Goldberg AL. Proteasome
inhibitors: from research tools to drug
candidates. Chem Biol 2001;8:739-58
21. Adams J. Potential for proteasome
inhibition in the treatment of cancer.
Drug Discov Today 2003;8(7):307-15
22. Zhu Y, Zhao X, Zhu X, et al. Design,
synthesis, biological evaluation, and
structure- activity relationship (SAR)
discussion of dipeptidyl boronate
proteasome inhibitors, part I:
comprehensive understanding of the SAR
of alpha-amino acid boronates.
J Med Chem 2009;52:4192-9
23. Mujtaba T, Dou Q. Advances in the
understanding of mechanisms and
therapeutic use of bortezomib.
Discov Med 2011;12:471-80
24. Shah MH, Young D, Kindler HL, et al.
Phase II study of the proteasome
inhibitor bortezomib (PS-341) in patients
with metastatic neuroendocrine tumors.
Clin Cancer Res 2004;10:6111-18
25. Kondagunta GV, Drucker B, Schwartz L,
et al. Phase II trial of bortezomib for
patients with advanced renal cell
carcinoma. J Clin Oncol 2004;22:3720-5
26. Markovic SN, Geyer SM, Dawkins F,
et al. A phase II study of bortezomib in
the treatment of metastatic malignant
melanoma. Cancer 2005;103:2584-9
27. Li R, Cui J, Zhu Y, et al. Tripetide
boronic acid or boronic ester, preparative
method and use thereof. Google Patents.
US13379142; 2010
28. Bernardini R, Bernareggi A, Cassara PG,
et al. Proteasome inhibitors and methods
of using the same. US8058262; 2011
. An interesting attempt to decrease
toxicity and increase bioavailability by
employing a protecting group on the
boronic acid moiety.
29. Olhava EJ, Danca MD. Proteasome
inhibitors. US13209511; 2011
30. Shenk KD, Paralati F, Bennett MK.
Compounds for immunoproteasome
inhibition. US0072422; 2013
31. Soppimath K, Pejaver S, Patel KR, et al.
Stable Bortezomib Formulations.
US0322763; 2012
32. Fostier K, De Becker A, Schots R.
Carfilzomib: a novel treatment in
relapsed and refractory multiple
myeloma. Oncol Targets Ther
2012;5:237
33. Kuhn DJ, Chen Q, Voorhees PM, et al.
Potent activity of carfilzomib, a novel,
irreversible inhibitor of the ubiquitin-
proteasome pathway, against preclinical
models of multiple myeloma. Blood
2007;110:3281-90
34. Demo SD, Kirk CJ, Aujay MA, et al.
Antitumor activity of PR-171, a novel
irreversible inhibitor of the proteasome.
Cancer Res 2007;67:6383-91
35. Kirk CJ, Jiang J. Use of Peptide
Epoxyketones for Metastasis Suppression.
US0035295; 2013
36. Shenk KD, Parlati F, Zhou HJ, et al.
Compounds for enzyme inhibition.
US8080576; 2011
37. Smyth MS, Laidig GJ. Compounds for
proteasome enzyme inhibition.
US8198270; 2012
Proteasome inhibitor patents (2010 -- present)
Expert Opin. Ther. Patents (2014) 24 (4) 11
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
MA
TY
AG
I on
01/
24/1
4Fo
r pe
rson
al u
se o
nly.
38. Smyth MS, Laidig GJ. Compounds for
enzyme inhibition. US8207125; 2012
39. Smyth MS, Laidig GJ. Compounds for
enzyme inhibition. US8207127; 2012
40. Kisselev A, Filippov DV, Overkleeft H.
Inhibitors of the trypsin-like site of the
proteasome and methods of use thereof.
US8455431; 2013
.. A very insightful paper into the
usefulness of T-L active site inhibitors
as well as unique compounds with
high selectivity for the T-L active site.
41. US Food and Drug Administration.
Approved Drugs - Carfilzomib.
2012. Available from: http://www.fda.
gov/Drugs/InformationOnDrugs/
ApprovedDrugs/ucm312945.htm
42. Guo S, Lu J, Subramanian A, et al.
Microarray-assisted pathway analysis
identifies mitogen-activated protein
kinase signaling as a mediator of
resistance to the green tea polyphenol
epigallocatechin 3-gallate in her-2/
neu--overexpressing breast cancer cells.
Cancer Res 2006;66:5322-9
43. Sun CL, Yuan JM, Koh WP, et al.
Green tea, black tea and breast cancer
risk: a meta-analysis of epidemiological
studies. Carcinogenesis 2006;27:1310-15
44. Sartippour MR, Heber D, Ma J, et al.
Green tea and its catechins inhibit breast
cancer xenografts. Nutr Cancer
2001;40:149-56
45. Landau JM, Wang ZY, Yang GY, et al.
Inhibition of spontaneous formation of
lung tumors and rhabdomyosarcomas in
A/J mice by black and green tea.
Carcinogenesis 1998;19:501-7
46. Horie N, Hirabayashi N, Takahashi Y,
et al. Synergistic effect ofgreen tea
catechins on cell growth and apoptosis
induction in gastric carcinoma cells.
Biol Pharm Bull 2005;28:574-9
47. Bettuzzi S, Brausi M, Rizzi F, et al.
Chemoprevention of human prostate
cancer by oral administration of green tea
catechins in volunteers with high-grade
prostate intraepithelial neoplasia:
a preliminary report from a one-year
proof-of-principle study. Cancer Res
2006;66:1234-40
48. Kemberling J, Hampton JA, Keck RW,
et al. Inhibition of bladder tumor growth
by the green tea derivative
epigallocatechin-3-gallate. J Urol
2003;170:773-6
49. Smith DM, Daniel KG, Wang Z, et al.
Docking studies and model development
of tea polyphenol proteasome inhibitors:
applications to rational drug design.
Proteins 2003;54:58-70
50. Nam S, Smith DM, Dou QP. Ester
bond-containing tea polyphenols potently
inhibit proteasome activity in vitro and
in vivo. J Biol Chem 2001;276:13322-30
51. Bonfili L, Cecarini V, Amici M, et al.
Natural polyphenols as proteasome
modulators and their role as anti-cancer
compounds. FEBS J 2008;275:5512-26
52. Chan TH, Dou QP. Polyphenol
compounds for inhibiting proteasome
and uses thereof. US12968759; 2010
53. Chan TH, Lam WH, Chow LMC, et al.
(-)-epigallocatechin gallate derivatives for
inhibiting proteasome. US8193377; 2012
54. Dou QP, Chan TH, Smith DM.
Polyphenol proteasome inhibitors,
synthesis, and methods of use.
US13271058; 2011
55. Milacic V, Chen D, Ronconi L, et al.
A novel anticancer gold(III)
dithiocarbamate compound inhibits the
activity of a purified 20S proteasome and
26S proteasome in human breast cancer
cell cultures and xenografts. Cancer Res
2006;66:10478-86
56. Milacic V, Dou QP. The tumor
proteasome as a novel target for gold
(III) complexes: implications for breast
cancer therapy. Coord Chem Rev
2009;253:1649-60
57. Cvek B, Milacic V, Taraba J, et al. Ni
(II), Cu (II), and Zn (II)
diethyldithiocarbamate complexes show
various activities against the proteasome
in breast cancer cells. J Med Chem
2008;51:6256-8
58. Frezza M, Hindo SS, Tomco D, et al.
Comparative activities of nickel (II) and
zinc (II) complexes of asymmetric
[NN O] ligands as 26S proteasome
inhibitors. Inorg Chem 2009;48:5928-37
59. Daniel KG, Gupta P, Harbach RH,
et al. Organic copper complexes as a new
class of proteasome inhibitors and
apoptosis inducers in human cancer cells.
Biochem Pharmacol 2004;67:1139-51
60. Daniel KG, Chen D, Orlu S, et al.
Clioquinol and pyrrolidine
dithiocarbamate complex with copper to
form proteasome inhibitors and apoptosis
inducers in human breast cancer cells.
Breast Cancer Res 2005;7:R897-908
61. Milacic V, Jiao P, Zhang B, et al. Novel
8-hydroxylquinoline analogs induce
copper-dependent proteasome inhibition
and cell death in human breast cancer
cells. Int J Oncol 2009;35:1481-91
62. Hindo SS, Frezza M, Tomco D, et al.
Metals in anticancer therapy: copper (II)
complexes as inhibitors of the 20S
proteasome. Eur J Med Chem
2009;44:4353-61
63. Zuo J, Bi C, Fan Y, et al. Cellular and
computational studies of proteasome
inhibition and apoptosis induction in
human cancer cells by amino acid schiff
base-copper complexes. J Inorg Biochem
2013;118:83-93
64. Hollingshead RGW. Studies on
derivatives of 8-hydroxyquinoline (oxine).
The sensitivity and selectivity of
5-nitroso-oxine and 2-methyl-5-nitroso-
oxine towards the group IIIB metals.
Anal Chim Acta 1955;12:401-7
65. Schimmer AD. Use of 5AHQ and
bortezomib for the treatment of
hematological diseases. US13203878;
2010
66. Sheshbaradaran H. Combination therapy
with A proteasome inhibitor and a
gallium complex. US0096068; 2013
67. Feling RH, Buchanan GO, Mincer TJ,
et al. Salinosporamide A: a highly
cytotoxic proteasome inhibitor from a
novel microbial source, a marine
bacterium of the new genus Salinospora.
Angew Chem Int Ed 2003;42:355-7
68. Fenical W, Jensen PR, Palladino MA,
et al. Discovery and development of the
anticancer agent salinosporamide
A (NPI-0052). Bioorg Med Chem
2009;17:2175-80
69. Lam KS, Lloyd GK, Neuteboom STC,
et al. From natural product to clinical
trials: NPI-0052 (salinosporamide A), a
marine actinomycete-derived anticancer
agent. Chapter 12. Nat Prod Chem
Drug Discov 2010;355-73
70. Macherla VRR, Potts BC, Manam RR,
et al. Proteasome inhibitors. US8227503;
2012
71. Ling T, Macherla VRR, Potts BC, et al.
Total synthesis of salinosporamide A and
analogs thereof. US8067616; 2011
72. Fenical WH, Jensen PR, Mincer TJ,
et al. Salinosporamides and methods for
use thereof. US8217072; 2012
73. Chauhan D, Singh A, Brahmandam M,
et al. Combination of proteasome
R. Metcalf et al.
12 Expert Opin. Ther. Patents (2014) 24(4)
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
MA
TY
AG
I on
01/
24/1
4Fo
r pe
rson
al u
se o
nly.
inhibitors bortezomib and NPI-0052
trigger in vivo synergistic cytotoxicity in
multiple myeloma. Blood
2008;111:1654-64
74. Ruiz S, Krupnik Y, Keating M, et al.
The proteasome inhibitor NPI-0052 is a
more effective inducer of apoptosis than
bortezomib in lymphocytes from patients
with chronic lymphocytic leukemia.
Mol Cancer Ther 2006;5:1836-43
75. Miller CP, Ban K, Dujka ME, et al.
NPI-0052, a novel proteasome inhibitor,
induces caspase-8 and ROS-dependent
apoptosis alone and in combination with
HDAC inhibitors in leukemia cells.
Blood 2007;110:267-77
76. Miller CP, Rudra S, Keating MJ, et al.
Caspase-8 dependent histone acetylation
by a novel proteasome inhibitor, NPI-
0052: a mechanism for synergy in
leukemia cells. Blood 2009;113:4289-99
77. Sallam AA, Ramasahayam S, Meyer SA,
et al. Design, synthesis, and biological
evaluation of dibromotyrosine analogues
inspired by marine natural products as
inhibitors of human prostate cancer
proliferation, invasion, and migration.
Bioorg Med Chem 2010;18:7446-57
78. Mudit M, Khanfar M, Muralidharan A,
et al. Discovery, design, and synthesis of
anti-metastatic lead phenylmethylene
hydantoins inspired by marine natural
products. Bioorg Med Chem
2009;17:1731-8
79. Lawrence HR, Sebti SM, Ozcan S, et al.
Proteasome chymotrypsin-like inhibition
using PI-1833 analogs. WO129564;
2012
80. Lawrence H, Ge Y, Sebti S, et al.
Proteasome inhibitors having
chymotrypsin-like activity. WO102286;
2010
81. Bachovchin W, Lai HS, Poplawski S,
et al. FAP-activated proteasome
inhibitors for treating solid tumors.
WO033396; 2013
.. An interesting patent on targeting
certain types of cancer cells.
82. Scanlan MJ, Raj B, Calvo B, et al.
Molecular cloning of fibroblast activation
protein alpha, a member of the serine
protease family selectively expressed in
stromal fibroblasts of epithelial cancers.
Proc Natl Acad Sci 1994;91:5657-61
83. Ravasz E, Somera AL, Mongru DA,
et al. Hierarchical organization of
modularaity in metabolic networks.
Science 2002;297:1551-5
84. Jeong H, Tombor B, Albert R, et al. The
large-scale organization of metabolic
networks. Nature 2000;407:651-4
85. Barabasi AL, Oltvai ZN. Network
biology: understanding the cell’s
functional organization. Nat Rev Genet
2004;5:101-13
86. Ma H, Zeng AP. Reconstruction of
metabolic networks from genome data
and analysis of their global structure for
various organisms. Bioinformatics
2003;19:270-7
87. Taylor KB. Enzyme kinetics and
mechanisms. 2002; Kluwer Academic
Publishers, Norwell: MA, USA
88. Gottesman MM. Mechanisms of cancer
drug resistance. Annu Rev Med
2002;53:615-27
89. Dean M, Fojo T, Bates S. Annual review
of medicine. Tumour stem cells and drug
resistance. Nat Rev Cancer
2005;5:275-84
90. Fertig G, Friess T, Klein C, et al.
Combination therapy of a type II
anti-CD20 antibody with a proteasome
inhibitor. US0219549; 2012
91. Forster C. Means and methods for
treating ischemic conditions.
US0245078; 2012
92. Piva R, Ruggeri B, Williams M, et al.
CEP-18770: a novel, orally active
proteasome inhibitor with a tumor-
selective pharmacologic profile
competitive with bortezomib. Blood
2008;111:2765-75
93. Gallerani E, Zucchetti M, Brunelli D,
et al. A first in human phase I study of
the proteasome inhibitor CEP-18770 in
patients with advanced solid tumours and
multiple myeloma. Eur J Cancer
2013;49(2):290-6
94. Ruggeri B, Seavey M. Proteasome
inhibitor delanzomib for use in the
treatment of lupus. WO119056; 2012
95. Li R, Yang N, Zhang L, et al. Inhibition
of Jak/STAT signaling ameliorates mice
experimental nephrotic syndrome.
Am J Nephrol 2007;27:580-9
96. Nikrad M, Johnson T, Puthalalath H,
et al. The proteasome inhibitor
bortezomib sensitizes cells to killing by
death receptor ligand TRAIL via
BH3-only proteins Bik and Bim.
Mol Cancer Ther 2005;4:443-9
97. Williams S, Pettaway C, Song R, et al.
Differential effects of the proteasome
inhibitor bortezomib on apoptosis and
angiogenesis in human prostate tumor
xenografts. Mol Cancer Ther
2003;2:835-43
98. Broyl A, Corthals SL, Jongen JL, et al.
Mechanisms of peripheral neuropathy
associated with bortezomib and
vincristine in patients with newly
diagnosed multiple myeloma:
a prospective analysis of data from the
HOVON-65/GMMG-HD4 trial.
Lancet Oncol 2010;11:1057-65
99. Nawrocki ST, Carew JS, Pino MS, et al.
Bortezomib sensitizes pancreatic cancer
cells to endoplasmic reticulum stress-
mediated apoptosis. Cancer Res
2005;65:11658-66
100. Lonial S, Waller EK, Richardson PG,
et al. Risk factors and kinetics of
thrombocytopenia associated with
bortezomib for relapsed, refractory
multiple myeloma. Blood
2005;106:3777-84
101. Zangari M, Yaccoby S, Cavallo F, et al.
Response to bortezomib and activation of
osteoblasts in multiple myeloma.
Clin Lymphoma Myeloma
2006;7:109-14
102. Takeda K, Mori A, Yanagida M.
Identification of genes affecting the
toxicity of anti-cancer drug bortezomib
by genome-wide screening in S. pombe.
PloS One 2011;6:e22021
103. McConkey DJ. A novel role for a
familiar protein in apoptosis induced by
proteasome inhibition. Cancer Cell
2008;14:1-2
104. Shoshan MC, Linder S. Target specificity
and off-target effects as determinants of
cancer drug efficacy. Expert Opin Drug
Metab Toxicol 2008;4(3):273-80
105. Dick LR, Fleming PE. Building on
bortezomib: second-generation
proteasome inhibitors as anti-cancer
therapy. Drug Discov Today
2010;15:243-9
106. Arastu-Kapur S, Anderl JL, Kraus M,
et al. Nonproteasomal targets of the
proteasome inhibitors bortezomib and
carfilzomib: a link to clinical adverse
events. Clin Cancer Res
2011;17:2734-43
107. Chen S, Blank JL, Peters T, et al.
Genome-wide siRNA screen for
modulators of cell death induced by
Proteasome inhibitor patents (2010 -- present)
Expert Opin. Ther. Patents (2014) 24 (4) 13
Exp
ert O
pin.
The
r. P
aten
ts D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y U
MA
TY
AG
I on
01/
24/1
4Fo
r pe
rson
al u
se o
nly.
proteasome inhibitor bortezomib.
Cancer Res 2010;70:4318-26
108. Nickeleit I, Zender S, Sasse F, et al.
Argyrin A reveals a critical role for the
tumor suppressor protein p27 in
mediating antitumor activities in
response to proteasome inhibition.
Cancer Cell 2008;14:23-35
AffiliationRainer Metcalf1, Latanya M Scott2,
Kenyon G Daniel*1,4 & Q Ping Dou†3,4
†,*Authors for correspondence1Moffitt Cancer Center, Chemical Biology Core,
12902 Magnolia Dr SRB3, Tampa, FL 33612,
USA2Moffitt Cancer Center, Office of Technology
Management and Commercialization,
12902 Magnolia Dr MRC-TTO Tampa,
FL 33612, USA3Wayne State University, Hudson Webber
Cancer Research Center, The Developmental
Therapeutics Program, 4100 John R. Street
Room 540.1, Detroit, MI 48201, USA
Tel: +1 813 745 5734;
E-mail: [email protected] State University, Karmanos Cancer
Institute, 540.1 HWCRC, 4100 John R Road,
Detroit, MI 48201, USA
Tel: +1 313 576 8301;
Fax: +1 313 576 8307;
E-mail: [email protected]
R. Metcalf et al.
14 Expert Opin. Ther. Patents (2014) 24(4)
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I on
01/
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