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SRI International Biosciences
Drug Discovery
For more than six decades, SRI has been a major provider of drug discovery
and development services to pharmaceutical and biotechnology companies,
academia, foundations, and government agencies. Through collaborations
with partnering companies and organizations, drugs discovered and developed
by SRI include: Halfan® (halofantrine), a malaria treatment; Vidarabine (trade
names VIRA-A and Ara-A), an antiviral drug active against Herpes simplex and
Varicella zoster viruses; Targretin® (bexarotene) and, most recently, Folotyn®
(pralatrexate), SRI cancer drugs to treat various lymphomas.
SRI’s interdisciplinary team combines expertise in molecular biology;
biochemistry; immunology; medicinal, synthetic, and process chemistry;
pharmacology; computer-aided drug design; molecular modeling; and
assay development for drug discovery and preclinical development.
Whether a single, focused study is required or a comprehensive “turn-key”
program, SRI provides the capabilities necessary to assist clients in the
translation of promising therapeutic candidates for indications involving, but
not limited to, infectious disease, oncology, neuroscience, and immunology
and inflammation.
Research on Disease Mechanisms
Clinical Analysis Laboratory
From Idea to IND®
Drug Metabolism, Pharmacokinetics, & Toxicology Services
PreclinicalDevelopment Planning & Regulatory Services
Pharmaceutical Sciences
Drug Discovery
Learn more
Infectious Disease page 5
Immunology & Inflammation page 4
Neuroscience page 6
Oncology / Cancer page 7
AdditionalDiscoveryCapabilities page 7
Target Validation & Assay Development page 2
Lead Identification & Optimization page 3
Leverage SRI’s experience for your success!
Cell- Based Assays
• Cellviability/compound cytotoxicityassays
• Apoptosis
• Autophagy
• RNAi-basedtargetvalidation
• Intracellularpathogenassays
• Cellularreporterassays
Mechanism-Based Animal Models
• Collagen-inducedarthritis
• Spontaneousdiabetes
• Experimentalautoimmune encephalomyelitis
• Inflammatoryboweldisease
• siRNA
Design and Validation of Biochemical and Cellular Screens
• Uniquemolecularlibrariesfortargetscreeningthroughcombinatorial chemistry
SRI has extensive experience in the identification of novel targets, the discovery of new molecules to interrogate those targets, and the elaboration of new molecular entities into lead compounds for clinical evaluation. SRI has successfully played a major role in translating more than 100 small molecules, biologics, and vaccines through Investigational New Drug (IND) applications into Phase I clinical trials.
SRI’s approach to identifying a new target starts by defining its molecular signature with assays such as those listed below or assays developed to address a specific target. Once cell-based effects are established, we can use affinity chromatography, with the compound on a matrix, to pull out and identify proteins that interact with it.
Target Validation and Assay Development
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• Partnershipsforscale-upmanufacturingofdiagnosticreagentsandkits
Proteomics and Metabolomics
• Novelfluorescenceprobesforearlydetectionofdisease
• Shotgunandquantitativeapproaches
• Characterizationofpost-translationalmodifications
• Geneexpressionanalysis
` Reportergeneactivation/repression
` mRNAarraysandmiRNAarrays
Imaging and Analysis
• Specializedhistology
• Immunocytochemistry
• Fluorescencemicroscopy
• Transmissionandscanningelectronmicroscopy
• Quantitativeimageanalysis
• Noninvasivefluorescence,biolumines-cence,andX-rayimagingofrodents
SRI can apply these assays to a broad range of disease mechanisms and therapeutic classes.
Lead Identification and OptimizationSRI’s success in drug discovery is exemplified by our robust drug pipeline, with several marketed drugs, several in clinical and preclinical development, and numerous discovery programs. SRI has helped clients and partners advance well over 100 drugs into patient testing. Our laboratories routinely perform drug discovery through target identification and lead generation, computer-aided drug design, and directed library design to generate new small molecule leads. During lead optimization, our team can enhance the most promising compounds to improve effectiveness, diminish toxicity, and increase absorption.
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Screening Hits to Leads
• Targetidentification
• Mechanismofactionstudies
• High-throughputscreeningofsmall moleculesforinvitroefficacy
• Hitresynthesisandvalidation
• Pharmacophoreidentification
• Computationalmodelingforscaffold optimization
Lead Optimization
• Parallelandfocusedlibrarysynthesis
• StructureActivityRelationships(SAR) development
• NMR-baseddrugdiscovery
• Solubility,lipophilicity,andionizabilitystudies
Custom Synthesis
• Multistepsynthesisofleadcandidates,syntheticintermediates,referencestandards,degradationproducts,ormetabolites
• Parallelandfocusedlibrarysynthesis ofscreeningsets
• Asymmetricsynthesis
• Processdevelopment
• Milligram-to-kilogramscaleup
Radiolabeled Synthesis
• Isotopiclabelingofcomplexmoleculeswithradioisotopes(14C, 3H, 125I, 32P, 33P, 35S)andstableisotopes(13C, 2H, 15N, 18O)
• Developmentofnewsyntheticmethodsforstereospecificisotopelabeling
• Biosyntheticlabelingofcomplex naturalproducts
• Consultingontheapplicationof isotopicallylabeledmolecules
Preformulation
• Physicochemicalandthermal characterization
• Excipientcompatibilitystudies
• High-throughputsolubilityscreening
• In vitrodrugpermeationstudies
Predictive ADMET Assays
• Membranepermeabilityand transporteractivity
• Drugmetabolismassays
• In vivomicrodialysis
• Targetorganandcytotoxicityassays
• Genetictoxicityscreens
• Invivopilotpharmacokinetic andtoxicityscreens
SRI’s Immunology and Inflammation group provides internationally recognized
services through all stages of drug discovery and development. With state-of-
the-art equipment, laboratory, and animal facilities, we can offer turnkey and
customized services to meet your needs, including assay development and
validation, research and drug discovery, preclinical development, and clinical
sample analysis.
Working with our Quality Control and Quality Assurance groups, we routinely
support GLP and cGMP studies.
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Assay Development and Validation
• In vitro and ex vivoassays (cellfunction/receptorbinding assays/compoundscreening)
• In vivoefficacystudies(animal modelsofinflammatorydisease)
• Customandclient-providedassays
• GLP-andcGMP-compliantstudies
Research and Drug Discovery
• In vitro and ex vivoevaluations ofimmunefunction
• Animalmodelsofautoimmunediseasesincludingdiabetes,inflammatoryboweldisease,multiplesclerosis, andrheumatoidarthritis
• In vivoefficacy,includingdesign ofcustomanimalmodels
• Specializedcompoundscreening inimmunecellsfromhumanandanimaltissues
Preclinical Development
• Assessmentofimmunogenicity (cellularandhumoral)
• Sampleanalysisforpharmacokineticsandtoxicokinetics
• Measurementofvaccineefficacy
• Immunotoxicologyevaluation
• Biomarkeranalysis
Analysis of Clinical Samples
• Immunoassays(measurementof biologicsforpharmacokinetics)
• Determinationofimmunogenicity (cellularandhumoral)
Common Techniques
• ELISA
• Cellularproliferationassays
• CytotoxicTLymphocyte(CTL)assay
• Mixed-lymphocytereaction(MLR)
• Clonalexpansionofprimary immunecells
• Flowcytometry(FACS):intracellularandcellsurfacestaining,cellcycleanalysis,andapoptosis
• AutomatedELISpotanalysis
• Magnetic-activatedcellsorting(MACS)
• Electrophoresisandimmunoblotting
• Receptorbindingassays
• DNAandRNAmolecularbiology techniques,eukaryoticcelltransfection
• RT-PCR,qualitativeandquantitative
• Immunohistochemistryand immunofluorescentstaining
Selected In Vivo Models
• Acuteandchroniccollagen-inducedarthritis
• AcuteandchronicDSS,TNBS/ Oxazolone,andspontaneous(IL-10-/-)inflammatoryboweldisease
• Activeandpassiveexperimental autoimmuneencephalomyelitis
• SpontaneousdiabetesinNODmice
REGULATORY/LICENSING APPROVALS
Select AgentsBSL-3 FacilityGLP and cGMP Compliance
Immunology & InflammationImageSources:Dr.Triche.NationalCancerInstitute
Infectious DiseaseInfectious diseases truly represent a global public health challenge; therefore,
the discovery of safe and effective therapeutics is imperative. At SRI, we
bring a wealth of experience and diverse scientific interests to our mission
of creating improved diagnostics, prophylactics and therapeutics for a wide
range of rare and neglected diseases and tropical diseases, and infectious
and biological threat agents, all of which seriously challenge global health.
Our capabilities include medicinal and synthetic chemistry; in vitro assay
development; and in vitro and in vivo drug efficacy screening against toxins
and bacterial, viral, and parasitic diseases (including CDC select agents) up
to BSL3 containment.
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In Vitro Efficacy Models
• Neglected&emergingpathogens
` TB(Mycobacteriumtuberculosis)drugscreening,including XDR/MDRstrains
` Influenzavirusstrains
` Parasiticdiseases,including LeishmaniasisandChagas
• Drug-resistantbacterialpathogens:
` HAandCA-MRSA,Acinetobacterspp.,Klebsiellaspp.,Pseudomonasspp.
• NIAIDcategoryA,BandCpathogensandselectagents:
` B.anthracis,Y.pestis,F.tularensis,Burkholderiaspp,C.burnetii, Brucellaspp.,Chlamydiaspp., Shigellaspp.,Rickettsiaspp., Listeriaspp,Vibriospp.
` Virusesincludingdengue,SARS,arenaviruses,Hantaan,RiftValleyFever,WestNile,Chikungunya,andotherencephalitis-causingviruses
` Toxinsincludingricin,botulinum,shigaandStaphylococcus enterotoxinB
• Food-bornepathogensincluding Salmonellaandenterohemorrhagic E.coli
• Hostresponseprofilesfollowing host-pathogeninteractions
In Vivo Efficacy Models
• Infectiousdiseasemodeldevelopment
• Mouseandferretmodels ofinfluenzainfection
• Smallanimalimaging
• Sepsismodels
Vector Biology
• Insecticideresistance
• Vectorcompetence
• Entomotherapeutics,theapplication ofinsect-derivedcompoundsasnoveltherapies
Customized Assay Development and Screening
Biomarker Discovery
Diagnostic Development
Radioactive Materials Controlled Substances AAALAC Accredited
ImageSources:RockyMountainLaboratories,NIAID,NIH
The Center for Neuroscience at SRI combines world-class basic science with contract research to provide an environment ideal for partnering with clients and for helping advance research and development programs. Our research programs in sleep, cognition, circadian rhythms, pain and addiction demonstrate our expertise using in vivo physiology and pharmacology, behavior, microdialysis, in vitro electrophysiology, neuroanatomy, and differential gene and protein expression techniques in various animal disease models. Our capabilities allow us to determine the efficacy of novel treatments on behavior and physiology, to investigate the neural mechanisms that underlie drug effects, and provide a translational approach to evaluate preclinical findings for CNS disorders.
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Neuroscience
In Vivo Pharmacology and Behavior
• Sleep/wakerecordingsandanalysis
• QuantitativeEEGanalysis
• Electromyogram(EMG)recordings
• Circadianrhythmsassessment
• Infra-reddigitalvideorecording
• Customneurosurgicalcapabilities
• Invivobrainmicrodialysis
• Intrathecaldrugdelivery
• Customperipheralsurgeries
In Vivo Models
• Ourrodentbehavioralmodelsincludebutarenotlimitedto:
` Acuteandchronicpain (hot-plate,tailflick,CCI;SNL)
` Drugaddiction(CCP,drugSA)
` Chronicalcoholism(bottle-choice)
` Motordisorders(rotarodtesting)
` Anxietyanddepression (openfieldtest,light/darkboxes)
` Learningandmemory (Morriswatermaze)
` Geneticmodelsofneurologicaldiseases(narcolepsy,Huntington’sdiseaseandAlzheimer’sdisease)
•Ournonhumanprimates(NHPs)areoperantlytrainedonbasicleverpressingand/orCANTAB™.Commontestassessmentsinclude,butarenotlimitedto:
` Workingmemoryattention
` Impulsivityantidepressantefficacy
` Pharmacokineticsideeffects
` Biochemical
In Vitro Assays
• Opiate(µ, ,k)andNOP
• Dopamine(D1, D2)
• Serotonin (5-HT2A,5-HT2B,5HT3,5-HT4)
• GABA,Benzodiazepine
• Adrenergic( 1, 2, 1, 2 )
• NMDA
• Sigma
• Nicotinicionchannels
In Vitro Neurophysiology and Neuropharmacology
• Brainslicerecordings
• Whole-cellcurrentandvoltageclamprecordings
• Analysisofmembranecurrentsandsynaptictransmission
• Fluorescenceanddifferentialinterfer-encecontrast(DIC)microscopy
• FLIPR®basedcalciumassays
Neuroanatomy
• Immunohistochemistry
• Insituhybridization(radioactiveandnonradioactiveprobes)
• Basichistologyandstainingtechniques
Gene and Protein Expression
• GeneChip®analysis
• Quantitativereal-timepolymerasechainreaction(qPCR)
• RNAisolationandanalysisofspecificbrainregions
In Vivo Microdialysis and Neurotransmitter Analysis
Freely-moving rodent studies can be performed under the following conditions:
• Awakeoranesthetized
• Singleordualprobeplacement
• Localperfusion(reversedialysis)
• Systemicdrugdelivery(IP,IV,PO,SC)orICV
• Combinedwithotherinvivotech-niques(lesionmodels)
• Monitoringotherbehavioralactivities
Quantitative analytical services of biological samples and perfusates are supported by instrumentation from ESA-Dionex, Inc. Our capabilities include:
• Monoamines(NE,DA,5-HT, andallmetabolites)
• Acetylcholine
• AminoacidsandGABA
• Adenosine
Biomarkers upon request
Biomarker Discovery
Diagnostics
Target Validation and Assay Development
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SRI’s Center for Cancer Research offers a collection of assays that can interrogate many cellular pathways. Our experienced staff works together with our clients to ensure that the most effective interdisciplinary approach is applied to their cancer drug discovery projects. We perform every step in the process, from target identification to selection of a candidate for preclinical development.
These integrated processes include: identification and validation of novel targets; development of assays; selection of leads guided by functional assays; exploration of structure-activity relationship (SAR) through medicinal chemistry; and compound optimization through iterative cycles of testing for drug-like properties and potency, finally resulting in identification of a molecule for development.
Oncology / Cancer
ADDITIONAL DISCOVERY CAPABILITIES
In Vitro Efficacy Assays Models
• Proliferation
• Cytotoxicity
• Apoptosis
• Autophagy
• Cellcycleanalysis
• Migrationandinvasion
• Angiogenesis
` Endothelialproliferation,migration,andtubeformation
` Ex ovochickchorioallantoic membraneassay(CAM)
In Vivo Efficacy Models
• Xenograftmodelsbasedonthe followinghumancelllines:
` Breastcancer
` Cervicalcancer
` Coloncancer
` Fibrosarcoma
` Glioblastoma
` Kidneycancer
Noninvasive imaging models
• Orthotopicstudies
` Humanbreastcancermodel
` Humanglioblastoma
` Humanprostatecancermodel
• Metastasisstudies
` Humanbreast
` Humanprostate
` Murinemelanoma
` Multiplemyeloma
Hypoxia Models
• Invitroresponses
• Invivoimagingandanalysis ofhypoxia
` Leukemia
` Livercancer
` Lungcancer
` Medulloblastoma
` Melanoma
` Myeloma
` Neuroblastoma
` Osteosarcoma
` Ovariancancer
` Pancreaticcancer
` Prostatecancer
` Tonguesquamouscarcinoma
• Syngeneicmousemodels
` Colon
` Melanoma
` Pancreaticcarcinoma
• Additionalcommercialcell linesuponrequest
•Radiotherapy
` Combinationefficacystudies
Cell and Molecular Imaging
Reproductive / Hormonal
Diabetes / Metabolic Diseases
Microdialysis Molecular Biology
Angiogenesis
Contact Us
SRI Biosciences 333 Ravenswood Avenue Menlo Park, CA 94025-34931.650.859.3000
Center for Advanced Drug ResearchSRI Shenandoah Valley 140 Research DriveHarrisonburg, VA 228021.540.438.6600
Toll-Free: 1.866.451.5998Email: [email protected]
www.sri.com/biosciences
Menlo Park Headquarters
SRI International333 Ravenswood AvenueMenlo Park, CA 94025-3493 1.650.859.2000
Washington, D.C.
SRI International 1100 Wilson Blvd., Suite 2800Arlington, VA 22209-3915
1.703.524.2053
www.sri.com
SRI International and Idea to IND are registered trademarks of SRI International. All other trademarks are the property of their respective owners.
Copyright 2011 SRI International. All rights reserved. 02/11
About SRI International BiosciencesSRI Biosciences carries out basic research, drug discovery and drug development, and provides contract services. SRI has all of the resources necessary to take R&D from Idea to IND®—from initial discovery to the start of human clinical trials—and specializes in cancer, immunology and inflammation, infectious disease, and neuroscience. SRI’s product pipeline has yielded marketed drugs, therapeutics currently in clinical trials, and additional programs in earlier stages. In its CRO business, SRI has helped government and other clients and partners advance well over 100 drugs into patient testing. SRI is also working to create the next generation of technologies in areas such as diagnostics, drug delivery, medical devices, and systems biology.
About SRI InternationalSilicon Valley-based SRI International is one of the world’s leading independent research and technology development organizations. SRI, which was founded by Stanford University as Stanford Research Institute in 1946 and became independent in 1970, has been meeting the strategic needs of clients and partners for more than 60 years.
Perhaps best known for its invention of the computer mouse and interactive computing, SRI has also been responsible for major advances in drug discovery and development, networking and communications, robotics, advanced materials, atmospheric research, education research, economic development, national security, and more. The nonprofit institute performs client-spon-sored research and development for government agencies, busi-nesses, and foundations. SRI also licenses its technologies, forms strategic alliances, and creates spin-off companies.