Discovery of RP-1664: A First-in-Class Orally Bioavailable, Selective PLK4 Inhibitor

PLK4 is a cell cycle-regulated kinase important for the biogenesis of centrioles and is known to be synthetically lethal with TRIM37 gene amplification. Previous attempts to inhibit PLK4 have been hampered by selectivity or ADME liabilities. The known inhibitor Centrinone B, while potent and selective, is metabolically unstable and lacks oral bioavailability. Assisted by structure-based drug design (SBDD), dramatic improvements in potency, selectivity and ADME properties were made to this structure, resulting in the identification of RP-1664, a potent inhibitor of PLK4 with an excellent pharmacokinetic profile in preclinical species. Kinome profiling demonstrated exquisite selectivity over related kinases, including AURKA/B and PLK1. RP-1664 disrupts centriole biogenesis in cancer cells, modulates pharmacodynamic readouts of PLK4 activity in xenograft tumor tissues, and is efficacious in multiple TRIM37 -amplified xenograft models. This first-in-class clinical candidate is currently being evaluated in Phase 1 clinical trials (NCT06232408) for treatment of advanced solid tumors.