2. Academic Validation
  3. Discovery of RP-1664: A First-in-Class Orally Bioavailable, Selective PLK4 Inhibitor

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

  • J Med Chem. 2025 Jun 12;68(11):10631-10647. doi: 10.1021/acs.jmedchem.5c00529.
Frédéric Vallée 1,  Matias Casás-Selves 1,  Monica Bubenik 1,  Martin Duplessis 1,  Boubacar Sow 1,  Catalina Suarez 1,  Bruno Sangiorgi 1,  Li Li 1,  Marc Hyer 1,  Robert Papp 1,  Marie-Eve Leclaire 1,  Alexander L Perryman 1,  Bingcan Liu 1,  Simon Surprenant 1,  Philippe Mochirian 1,  Victor Pau 2,  Zdenka Maderova 2,  Pavel Mader 2,  Shou Yun Yin 1,  Elliot Goodfellow 1,  Anne Roulston 1,  Rino Stocco 1,  Claude Godbout 1,  Prasamit Baruah 1,  Alexanne Bonneau-Fortin 1,  Joseph D Schonhoft 3,  Parham Nejad 3,  David Norman 4,  Vouy Linh Truong 4,  Sheldon Crane 4,  Mohamed A Attia 1,  Daniel Mao 2,  Frank Sicheri 2 5,  C Gary Marshall 3,  Michal Zimmermann 1,  David Bendahan 1,  Michel Gallant 1,  W Cameron Black 1
Affiliations

Affiliations

  • 1 Repare Therapeutics, Inc., 7210 Frederick-Banting, Ville St-Laurent, QC H4S 2A1, Canada.
  • 2 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
  • 3 Repare Therapeutics, 1 Broadway, 15th Floor, Cambridge, Massachusetts 02142, United States.
  • 4 Sygnature Discovery, 2350 rue Cohen Suite 201, Ville St-Laurent, QC H4R 2N6, Canada.
  • 5 Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
PMID: 40378279 DOI: 10.1021/acs.jmedchem.5c00529
Abstract

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.

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