title: Open innovation for phenotypic drug discovery: The PD2 assay panel.
abstract: Phenotypic lead generation strategies seek to identify compounds that modulate complex, physiologically relevant systems, an approach that is complementary to traditional, target-directed strategies. Unlike gene-specific assays, phenotypic assays interrogate multiple molecular targets and signaling pathways in a target "agnostic" fashion, which may reveal novel functions for well-studied proteins and discover new pathways of therapeutic value. Significantly, existing compound libraries may not have sufficient chemical diversity to fully leverage a phenotypic strategy. To address this issue, Eli Lilly and Company launched the Phenotypic Drug Discovery Initiative (PD(2)), a model of open innovation whereby external research groups can submit compounds for testing in a panel of Lilly phenotypic assays. This communication describes the statistical validation, operations, and initial screening results from the first PD(2) assay panel. Analysis of PD(2) submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD(2) have confirmed hit rates from 1.6% to 10%, with the majority of active compounds exhibiting acceptable potency and selectivity. Phenotypic lead generation strategies, in conjunction with novel chemical diversity obtained via open-source initiatives such as PD(2), may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.
authors.affiliation: Department of Quantitative and Structural Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA. jonathan_a_lee@lilly.com
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lee
authors.forename: Shaoyou
authors.initials: S
authors.lastname: Chu
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cox
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Sells Galvin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Peery
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Oliver
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oler
authors.forename: Tamika D
authors.initials: TD
authors.lastname: Meredith
authors.forename: Steven A
authors.initials: SA
authors.lastname: Heidler
authors.forename: Wendy H
authors.initials: WH
authors.lastname: Gough
authors.forename: Saba
authors.initials: S
authors.lastname: Husain
authors.forename: Alan D
authors.initials: AD
authors.lastname: Palkowitz
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Moxham
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D007328:Insulin; D047428:Protein Kinase Inhibitors; D050257:Tubulin Modulators; D051153:Wnt Proteins; D015739:Nocodazole