Discovery of an orally bioavailable and selective PKMYT1 inhibitor, RP-6306
Szychowski, J. et al. (2022) Discovery of an orally bioavailable and selective PKMYT1 inhibitor, RP-6306. J. Med. Chem. 65, 10251–284. DOI: 10.1021/acs.jmedchem.2c00552
Cyclins are a protein family that regulate cellular growth. They interact with cyclin-dependent kinases (CDKs) to initiate and control cell cycle progression. Protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) phosphorylates cyclin-dependent kinase 1 (CDK1), inhibiting its ability to trigger mitosis. When PKMYT1 is absent in tumors with CCNE1 amplification, checkpoint regulation is lost and can cause hyperactive CDK1, DNA damage, mitosis and cell death. Because of this, PKMYT1 is a therapeutic target for treating DNA damage-response cancers.
Previous research has not found PKMYT1 selective inhibitors, limiting research on pharmacological activity. This study worked to identify a potent, selective and orally bioavailable PKMYT1 inhibitor. Researchers screened 560 known kinase inhibitors and identified nonspecific inhibitor 1 as a potential lead. They then modified the compound structure to understand which aspects were essential to PKMYT1 activity and inhibition.
Researchers identified PKMYT1 cell-based potency, kinase selectivity and ADME (absorption, distribution, metabolism, and excretion) as key properties involved in PKMYT1 activity. Optimizing these properties yielded the selective and orally bioavailable PKMYT1 inhibitor RP-6306. In preclinical species studies, the compound had a favorable pharmacokinetic profile and has shown effectiveness in mouse xenograft models. Currently, RP-6306 is being used in Phase 1 clinical trials to study the pharmacological role of PKMYT1 in treating various solid tumors. This study shows how compound screening and modification can offer a pathway to generating a kinase inhibitor for clinical research.
Keywords: Cyclin, cyclin-dependent protein kinase, cell cycle, cancer, tumor, kinase inhibitor
