Small molecule induced protein degradation represents an exciting frontier in chemical biology. The development of small molecule protein degraders as therapeutics would significantly increase the accessible druggable space since a direct functional response to the binding of a molecule to a protein is not required. The challenge to translate the current tool molecules into potential therapeutics is, however, significant. This talk will outline the early work we have undertaken at GSK with bifunctional degraders (PROTACs) to develop the technology and to build a broader developability dataset with these molecules to build confidence that molecules with profiles consistent with progression through to candidate selection and beyond are achievable. As these molecules require simultaneous binding to both a target and E3 ligase complex, they will inevitably sit outside of perceived normal small molecule property space.  Relying on measured data rather than in silico prediction has been a critical element to this work.

Inducing protein degradation: A new paradigm for pharmaceutical intervention

248th National Meeting (2014)

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