PKMYT1 is an important regulator of CDK1 phosphorylation and is a compelling target for treatment certain types of DNA damage repair cancers. Unfortunately, no selective inhibitors have been previously identified for this kinase that would allow for pharmacological evaluation.  To address this need we conducted a focused screening effort that identified <b>RP-1068</b> as a weak PKMYT1 inhibitor. Structure-based drug design aided by co-crystal structures of several analogs allowed the introduction of a dimethylphenol that dramatically increased potency on PKMYT1. These dimethylphenol analogs were found to exist as Type III atropisomers that could be separated and profiled.  Optimization of cell-based potency, kinase selectivity, and ADME properties led to the identification of potent and selective inhibitors of PKMYT1 with acceptable pharmacokinetics in preclinical species. The first-in-class clinical candidate <b>RP-6306 </b>is currently being evaluated in Phase 1 clinical trials.

Discovery of orally bioavailable and selective PKMYT1 inhibitor RP-6306

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.