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 (PD2), 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 PD2 assay panel. Analysis of PD2 submissions indicates that chemical diversity from open source collaborations complements internal sources. Screening results for the first 4691 compounds submitted to PD2 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 PD2, may provide a means to identify compounds that modulate biology by novel mechanisms and expand the innovation potential of drug discovery.

Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders

“…That is, studies of biological actions performed in integrated systems rather than on single cells/proteins, and using a diversity of functional readouts from cellular signalling to neuritic outgrowth to synaptic transmission to (in vivo) behaviour (Lee et al, 2011;Penrod et al, 2011;SamsDodd, 2013;Swinney, 2014;Swinney and Anthony, 2011;Winchester et al, 2014). Although such studies can be performed under physiological conditions, the ability of agents to normalize a functional deficit is of greater interest.…”

“…In addition, chemistry has renounced the illusory gains of combinatorial chemistry, it is enriched by fragment-and antibody-based design, and is underpinned by more refined structural In addition, virtual screening (algorithms used to identify and predict novel bioactive compounds in the hit to lead phase) as well as in silico analysis of Structure-Activity-Relationships are more sophisticated in several ways. They now can, for example: exploit machine-learning techniques to refine the design of new chemical structures; benefit from improved insights into protein-folding and the dynamics of macromolecular complexes; integrate the roles of water molecules; and better predict genuine drug-like properties (Bottegoni et al, 2011;Gabrielsson et al, 2008;Hubbard, 2011;Keiser et al, 2009;Khatib et al, 2011;Lee et al, 2011;Schneider, 2010;Wager et al, 2010). Models will never be enough alone, but their predictions are increasingly converging with the actual syntheses of "wet" chemistry.…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Recently, screening has been conducted to identify compounds that can modulate additional AD-associated phenotypes such as Aβ-induced cytotoxicity, tau protein levels, apolipoprotein E (apoE) secretion or apoE4 conformation, Ca 2+ signaling and neurogenesis in neuronal cell lines [22,[25][26][27][28][29][30]. Within industry-sponsored phenotypic screening initiatives, apoE stimulators for possible AD therapeutics have been pursued by Eli Lilly's Phenotypic Drug Discovery Initiative (PD2) [31]. As screening data are not publically available, the initiative has made limited contributions to scientific knowledge in academia or to the public at large.…”

“…As screening data are not publically available, the initiative has made limited contributions to scientific knowledge in academia or to the public at large. The Lilly Initiative uses an astrocytoma cell line, CCF-STTG1 (vs primary astrocytes) [31,32]. It is conceivable that the screen identified false positive hits or missed a number of hits (false negatives) that may be preferentially active in primary cells and more physiological cell models, as certain compounds have been found to exert biological activities only in physiologically relevant cells but not in transformed cell lines [33].…”

Perspective on the Discovery and Scientific Impact of p38 MAP Kinase

“…So in many ways, this was an early example of the "open innovation" model that is very much in vogue these days. 49,50 In this model, tool compounds and molecular reagents are shared between academia and industry to foster precompetitive research to rapidly understand the role of a potential new target in many different biological systems, something that would be beyond the resources and expertise of any one laboratory.…”