9 28-2012 surveys phenotypic drug discovery sig

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Phenotypic Drug Discovery Forum/SIG Sept 28, 2012

Text of 9 28-2012 surveys phenotypic drug discovery sig

  • 1. Phenotypic Drug Discovery SIG Results from Survey Monkey September 28, 2012

2. About the SurveyThe Phenotypic Drug Discovery LinkedIN group has grown to over 350 memberssince its start in Mid May and is composed of a diverse population representingscientists, service/technology providers, and bio-entrepreneurs. With the helpof Lynn Valastyan and Francis Willard two surveys were developed to providegeneral information about the PDD SIG membership in general and to betterestimate the use and impact of phenotypic approaches by scientists.Survey responses have hit a plateau so it is probably time to publicize thecomplete results of both surveys. The data from the survey cannot bestatistically significant with less than 10% of the PDD SIG membershipresponding. Although the response was initially disappointing, Nan Hallock(Director of Publishing for SLAS) indicated that surveys were like letters to theeditors.not too many people actively participate, but many are interested.Hopefully members of the PDD SIG will find the results interesting..Jonathan LeeSeptember 28, 2012 3. PHENOTYPIC ASSAY SURVEY-1: ALLLINKEDIN PDD SIG MEMBERS 4. How can the Phenotypic Drug Discovery SIGLinkedIn site better serve your needs? Discussion forum is very helpful to follow progress in the area Networking and leads to capital investors. Keep the discussion going Exchange ideas and promote concept Understand hurdles identified by others. Sharing of practicalimplementation techniques. Progression of phenotypic-based projectsintothe clinic. By somehow getting more coal-face medchemists to join in! I was impressed with excellent discussions posted by finest scientists inthe field. Adding presentations that highlight the PSA if any would beinteresting. The set of very good and relevant topics that were raised up recently. Itprovided very useful sharing of information and stimulated interestingdiscussion. A section or catalog of PSA resources, e.g. service providers, pre-competitive consortia, academic core labs, would be helpful. 5. How can the Phenotypic Drug Discovery SIGLinkedIn site better serve your needs? The discussions on the site are extremely useful to me as a youngscientist in academia. The site would be better if we had some sortof member directory so that we may more easily find people ofcertain expertise and network (if one wishes to be involved in sucha network). Monthly or weekly compilation of all relevant papers in the area ofPDD Provide catalogue of available phenotypic capabilities and assayswith contact names Its too late to serve my personal needs, but for the needs of manyothers, it we should discuss new business models (including fundingsources) to reintegrate PDD into mainstream drug discovery. Thismay not seem natural for the primarily scientific bent of thisgroup, but if scientists dont get more savvy and assertive in thebusiness, satisfactory change can not occur. 6. PHENOTYPIC ASSAY SURVEY-2: RESEARCHSCIENTISTS (PAST AND PRESENT) 7. What significant achievements and or obstacles havebeen encountered when using phenotypic approachesfor target identification or si/shRNA screening? Uniformity across the board for acceptable bioassays. Harmonization ofprotocols for PSA in target discovery and validation. The quality of libraries have been questionable (especially Qiagen). Offtarget effects are troublesome and require several individual oligos pergene. The cellular response is variable and population-based analysis isrequired. Transfecting some cell types can be challenging. There is no realnegative control in siRNA screens, since all oligo will have some sort ofeffect. Obtaining a good base line is difficult, probably the best is themode or median of the entire library screen omitting positive controls. reproducible results Not all responses are direct effects - both mechanistic and siRNAnonspecificity issues. Obstacle: disconnect between mammalian cells and yeast genetic screensfor small molecule TID. Translation os siRNA results into shRNA results for stable cell generation intarget validation studies 8. Achievements: always found known genes in the list of potential functional genes.Obstacles: -Very low confirmation rate for the whole list of genes in functional screen.-Never sure that the siRNA against target will work and demonstrate effect significantto produce detectable phenotype. - Problem with the selection of the hits from thelist to follow up on. Obstacle: relative cost and need for larger collaborations Acheivement: proof ofconcept on modification of a key pathway cells/tissues specifically mimicking humandisease phenotypes. We are just starting target identification work, however a strategy using geneticmethods are already in place. Challenges: library preperation and throughput across assays formats, Validation ofhits. Achievement validated novel targets identified. Target identification in phenotypic settings is not a trivial exercise - theres alwaysconcern that interactions seen are not actually those which are relevant to theobserved phenotype. Achievements: many novel, useful targets or pathways discovered. Useless targetseliminated. Novel compound-target pairings discovered that were developed intobiological probes and new screens that couldnt have been developed any other way.Obstacles: 1, managerial/investor resistance to starting program without predefinedtarget(s) and screen(s) specifically directed at the predefined target(s); 2,managerial/investor resistance to doing what looks to them like "just tooldevelopment 9. What significant achievements and or obstacles have beenencountered when using phenotypic approaches for drugdiscovery? Achievement- whole cell activity obtained Obstacle- deciphering of biological target has been cumbersome forbiology colleagues. Acceptance for peer-review funding. If you have specific NIH study sections that are interested in promoting PSA,it will be much appreciated. Processing time for a thorough image analysis is challenging, requires powerful computer clusters. Statisticalanalysis of objects within populations is challenging from a computational point of view as files comprisingseveral billion lines need to be processed. This requires computers with either large RAM or much free disk spacefor temp files. Visualisation of data is complex (how to display population distributions of various phenotypes?).Statistic methods to derive probabilities of phenotypes and test of population results. just getting started, target deconvoltion is currently our largest concern Acheivement = small molecule with novel MOA Obstacle = chemist Hard task to convince managers that PSA could be valuable and successfull for finding drugs with new MOA.Mentalities are still target oriented ! Identifying the molecular target. Of course, there is not agreement if this is necessary, but it is very helpful forpublication in a highend journal (this is a University). Identified 4 compounds from Prestwick library as non-DA symptomatic augmentation therapy for Parkinsonsdisease Achievements: identification of small molecules with cellular activity producing desired pheontype made celltarget validation and in vivo relevance more convincing, plus delivered valid tool compounds and cellularsystems to feed into the DD program. Obstacles: The chemical matter used in the the phenotype screen was notof good drug discovery quality (i.e. chemotypes unsuitable for development) necessitating a follow up todiscover better chemcial matter against the target. This was because as an academic group we did not haveaccess to good pharma collections but rather just the (cheap) off the shelf combichem library. 10. Achievements: new target and biology were found for anti-TB drug discovery. New scaffolds in characterization forHCV drug discovery. Two completed successful phenotypic siRNA screening discovered new functional genes.Obstacles: secondary assays are not ready after primary assay is done mostly because potential mechanisms andtargets are not known Obstacle: timing and throughput issues; longer learn and confirm med. chem. cycle AChievement: bettwrunderstanding of pre-ADME issues and enablement of a proof of concept and proof of relevance in patient derivedtissues i.e. a clinical trial in a test-tube on modulation of the disease phenotype. Assays of sufficient quantitative quality have been set up so as to perform SAR using phenotypic assays Achievements: Identified molecules which modulated in vitro and in vivo biology and easily differentiated fromstandard of care. Identified cellular processes not previously associated with therapeutic biology. Demonstratedthat phenotypic assays can provide evidence of compound SAR, can successfully utilize chemoinformatics miningmethods, and can be statistically validated. Phenotypic assays can be as operationally robust as biochemical assaysyet interrogate multiple molecular targets in a native context and without preconceptions of target validation.Obstacles: Compound drug-ability and metabolism issues encountered (like biochemical approaches). Compoundprioritization can be difficult. Phenotypic approaches may lead to unexpected findings relevant to the biologyresulting in flow scheme modification and timeline delays. Obstacles: Flat in vitro SAR; Low hit rate; High hit rate; Lack of a experience/strategy/knowledge for prosecutinghits. Target-directed mindsets that are inherently biased against PDD- both in bench scientists and themanagement. Overselling of the concept by senior management. Achievements: novel mechanisticallydifferentiated compounds for therapeutically relevant assays. Often the comparable target-based projects havemajor druggability issues. Challenges: Implementation of informatics workflows to collate multiparametric high-content data. Throuput forscreening compound and combinations across multiple assay formats/cell models. Development of bespoke imageanalysis algorithms to extract quantitative data from novel (