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.