The Phenotypic Drug Discovery LinkedIN subgroup has grown to over 300 members since its start in mid-May 2012 and is composed of a diverse population representing scientists, service/technology providers and bio-entrepreneurs. The group has finished its major growth phase and conducted a simple survey to learn more about themselves.

1. PDD Forum Survey:
Initial results 9/8/2012

6. Comments
• …we should discuss new business models (including funding sources) to reintegrate PDD into
mainstream drug discovery. This may not seem natural for the primarily scientific bent of this group,
but if scientists don't get more savvy and assertive in the business, satisfactory change can not
occur.
• Target identification in phenotypic settings is not a trivial exercise - there's always concern that
interactions seen are not actually those which are relevant to the observed phenotype.
• Target identification can be difficult to do rapidly, which puts pressure on the team as a whole.
• Challenges: Implementation of informatics workflows to collate multiparametric high-content data.
Throuput for screening compound and combinations across multiple assay formats/cell models.
Development of bespoke image analysis algorithms to extract quantitative data from novel (3D, co-
culture) assay formats.
• siRNA Achievements: many novel, useful targets or pathways discovered. Useless targets
eliminated. Novel compound-target pairings discovered that were developed into biological probes
and new screens that couldn't have been developed any other way. Obstacles: 1,
managerial/investor resistance to starting program without predefined target(s) and screen(s)
specifically directed at the predefined target(s); 2, managerial/investor resistance to doing what
looks to them like "just tool development

7. Comments
• Achievements: discovering novel chemical scaffolds with a desirable balance of pharmacological
properties acting on previously undiscovered or intractable targets. Obstacles: 1,
managerial/investor resistance to advancing leads without a defined or fashionable mechanism of
action. 2, managerial/investor resistance to starting programs not predicated on screening against
fashionable target(s).
• Identified molecules which modulated in vitro and in vivo biology and easily differentiated from
standard of care. Identified cellular processes not previously associated with therapeutic biology.
Demonstrated that phenotypic assays can provide evidence of compound SAR, can successfully
utilize chemoinformatics mining methods, and can be statistically validated. Phenotypic assays can
be as operationally robust as biochemical assays yet 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). Compound prioritization can be
difficult. Phenotypic approaches may lead to unexpected findings relevant to the biology resulting 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
prosecuting hits. Target-directed mindsets that are inherently biased against PDD- both in bench
scientists and the management. Overselling of the concept by senior management. Achievements:
novel mechanistically differentiated compounds for therapeutically relevant assays. Often the
comparable 'target-based' projects have major druggability issues.