The application of cross-disciplinary phenotypic discovery to investigate emerging biology is a powerful and exciting approach to discover new biological targets and molecules and has been shown to make a significant impact on drug discovery as a complementary approach to target-based approaches. The increased access to patient-derived cells or tissues and developments in induced pluripotent stem (iPS) cell technology coupled to more complex cellular systems such as three-dimensional cultures or organs on a chip is providing opportunities for more disease-relevant screens. Incorporating advances in gene editing and screening technologies such as single-cell imaging as well as developments in target identification and mode of action elucidation is further enhancing the opportunities to discover human disease relevant biological targets and hit molecules. Phenotypic discovery is a multi-disciplinary activity and this talk will describe our learnings across a number of screens including the essential requirements during assay development and the use of biologically annotated compound libraries. The talk will then illustrate research in emerging areas of biology to discover novel regenerative molecules in the arena of heart failure including the use of primary patient derived cells and cardiac organoids. Finally I will describe a phenotypic drug discovery project searching specifically for molecules which modulate the sphingolipid pathway and reduce glycosphingolipids. A cell-based high throughput screen searching for inhibitors of the sphingolipid pathway was developed and performed. Hits were confirmed and triaged using orthogonal assays and finally the target of the compounds was revealed. In addition the hit series had the potential to cross the blood brain barrier and achieve the required brain exposure and the compounds have subsequently been optimised to move forward into clinical trials. The lead compound was shown to be active in a range of in vivo models and hence offer a potential treatment option of Gaucher disease and synucleinopathies. Utilizing phenotypic screening with cellular models with strong translational links to human pathophysiology provides an opportunity to identify human disease-relevant biological targets and molecules with the potential to enhance efficacy and differentiate over standard of care to treat patients.

Phenotypic drug discovery: Probing emerging biology to delivering clinical candidates

255th National Meeting (2018)

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