UICentre Drug Discovery Workshop 2019
8:00 - 8:30am Continental Breakfast
8:30 - 9:15am Dave Swinney, Drug Discovery Consultant, Institute for Rare and Neglected
Phenotypic Drug Discovery: History, Evolution and Future
9:15 - 10:00am Jonathan Lee, Consultant, PDD 4 Patients
Best Practices for Phenotypic Drug Discovery: Lessons Learned and Novel
Mechanisms of Action from an Anti-angiogenesis Screen
10:00 - 10:45am Jim Audia, Executive Director, Chicago Biomedical Consortium
A Chemist’s Perspective on Phenotypic Drug Discovery
10:45 - 11:00am Break
11:00 - 11:45am Scott Warder, Principal Research Scientist, AbbVie
Translating Phenotypic Screening Hits to Mechanisms of Action and Therapeutics
11:45 - 12:30pm Natalie Dales, Director Global Discovery Chemistry, Novartis Institutes for
Phenotypic Drug Discovery in Spinal Muscular Atrophy: The Discovery and
Mechanistic Elucidation of LMI070 (branaplam)
12:30 - 1:15pm Panel Discussion
1:30 - 2:30pm Networking Reception
Note: Topics are subject to change
David C. Swinney: Phenotypic Drug Discovery: History, Evolution and Future
Astute empirical observation and chance (serendipity) have historically played large roles in the discovery of many new innovative medicines. Penicillin was discovered by the empirical observation of decreased bacterial growth in an unwashed petri dish. Empirical drug discovery, termed phenotypic drug discovery (PDD), continues to play a significant role in the discovery of First in Class (FiC) medicines, despite the focus on more rational reductionist strategies. At the core of phenotypic drug discovery is an unbiased selection of drug candidates without prior assumption as to how the candidate will work to change a pathological disease phenotype to a healthy phenotype. Currently there is much debate regarding the value and role of PDD in the evolution of drug discovery. My on-going analysis of FiC medicines indicates that different strategies have different strengths, and a strength of PDD is to identify novel molecular mechanisms of action and corresponding therapeutics. In the future PDD will continue to provide opportunities to discover innovative mechanisms (to identify what you do not know you do not know) and corresponding therapeutics, and thereby play an essential role in medical research. In this presentation I will discuss the definitions of drug discovery strategies, corresponding successes, strengths and weaknesses, and the opportunities and challenges to implement PDD as a strategy to increase drug discovery efficiency and productivity.
Jonathan Lee: Best Practices for Phenotypic Drug Discovery: Lessons Learned and Novel Mechanisms of Action from an Anti-angiogenesis Screen
Empirical or phenotypic drug discovery (PDD) is a target agnostic strategy which is experiencing a Renaissance in the pharmaceutical industry based on its successful track record in delivering first-in-class medicines stemming from novel biology. Although phenotypic screening may appear at first sight to be similar to target-based screening, there are some fundamental differences between the two approaches. Significantly, each active compound series from a phenotypic screen could, in principle, be acting through distinct molecular targets or signaling pathways. As a result, tactical considerations relevant to phenotypic assay operations include (1) the choice/design of an in vitro model system with the highest likelihood of translating to in vivo models/clinical studies, (2) pilot studies which test “tool compounds” with “known” biochemical or cellular activities and “standards of care” to elucidate underlying mechanisms related to the phenotypic biology in order to design compound triage flow schemes to identify unwanted MOAs and differentiate from SOC, and (3) consideration of the why/when/how of target/pathway identification/deconvolution studies.
The presentation will illustrate these points within the context of an anti-angiogenesis phenotypic screen which identified non-kinase leads that were differentiated from SOC and modulate angiogenesis through novel molecular targets/cellular mechanisms. Additionally, the long-term impact of PDD to provide (1) molecular tools to investigate the "unliganded" human proteome (estimated to be >90%) and (2) alternative strategies to the "me too" drug development Pharma philosophy (perhaps due to difficulties with target validation) will be presented.
Jim Audia: A Chemist’s Perspective on Phenotypic Drug Discovery
Phenotypic drug discovery (PDD) has traditionally been an important source for and the primary origin of many important classes of drugs. A recent analysis suggested that nearly two thirds of first-in-class small molecule drugs approved in the early 2000s could trace their origins to phenotypic screens, with the caveat that many of these agents were approved for infectious diseases. Despite this longstanding prominence in contemporary drug discovery, phenotypic approaches are enjoying a renewed emphasis across a broad swath of diseases as alternatives to more reductionist, target-based approaches, or increasingly as the source of novel targets for holistic drug discovery programs. In this talk, I will provide one chemist’s perspective on PDD, with some considerations on how the approach impacts the medicinal chemist as part of an overall drug discovery program from lead generation through clinical translation, with some further thoughts on increasing rigor, reproducibility and the likelihood of clinical success.
Scott E. Warder: Translating Phenotypic Screening Hits to Mechanisms of Action and Therapeutics
Phenotypic Drug Discovery (PDD) holds a potential to revolutionize the pharmaceutical industry, but its widespread implementation has been impeded by significant challenges. Emphasis on the importance of clinically translatable screening models has been a critical advancement. However, hit prioritization and target deconvolution strategies have not been reduced to practice, leaving many cellular active probes with unrealized potential. To address the hit progression issue, we have invested in technologies that discriminate between common and unprecedented mechanisms of action (MOA). In addition to defined assay panels, we have utilized profiling assays that enable comparison of activity signatures to large reference databases. For target deconvolution, we have implemented a combination of labeled and label-free probe technologies. Specifically, we have applied small molecule positive selection pooled whole genome CRISPR screening to reveal MOA details that not only enabled hit progression but also directed our target identification efforts. Examples of how we have addressed PDD challenges and lessons learned will be highlighted.
Natalie Dales: Phenotypic Drug Discovery in Spinal Muscular Atrophy: The Discovery and Mechanistic Elucidation of LMI070 (branaplam)
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional SMN protein resulting from the deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. A compensatory gene SMN2 carries a single nucleotide mutation leading to a mis-spliced RNA transcript and an unstable truncated SMN protein. We designed a set of phenotypic reporter gene assays to identify modulators of SMN2 splicing, specifically splicing changes at exon7. Through this work, we identified a pyridazine scaffold that provided the starting point for our discovery efforts leading to LMI070 (branaplam) and second generation scaffolds. In parallel, we elucidated the mechanism of these novel splicing modulators using a suite of cellular and biophysical approaches. LMI070/branaplam and related molecules correct the splicing defect in the SMN2 gene through stabilization of the spliceosome/pre-mRNA complex. This stabilization in turn leads to restoration of stable, full-length SMN protein. LMI070/branaplam is currently in clinical trials for SMA Type 1 patients.