The so-called undruggable space is an exciting area of potential growth for drug development. Undruggable proteins are defined as those unable to be targeted via conventional small molecule drugs. New modalities are being developed to potentially target these proteins. Targeted protein degradation (TPD) is one such new modality, which over the last two decades has moved from academia to industry. TPD makes use of the endogenous degradation machinery present in all cells, in which E3 ubiquitin ligases mark proteins for degradation via ubiquitin attachment. This session explored the challenges and perspectives of using protein degraders as novel therapeutic agents. The session began with a general introduction to the modality, followed by considerations in evaluating their on- and off-target toxicities including data from an IQ Consortium working group survey. Unique absorption, distribution, metabolism, and excretion (ADME) properties of degrader molecules were presented in relation to their effect on drug development and nonclinical safety assessment. The role of transgenic models in evaluating hemotoxicity associated with cereblon-based therapies was then discussed. A case study to derisk dose-limiting thrombocytopenia was also presented. Finally, a regulatory perspective on the challenges of having toxicity associated with protein degraders was presented.
Keywords: E3 ligase; PROTAC; VHL; cereblon; heterobifunctional molecules; molecular glues; protein degraders.