9o63 | pdb_00009o63
Crystal structure of PLK4 and RP1664 complex
Structural highlights
FunctionPLK4_HUMAN Serine/threonine-protein kinase that plays a central role in centriole duplication. Able to trigger procentriole formation on the surface of the parental centriole cylinder, leading to the recruitment of centriole biogenesis proteins such as SASS6, CENPJ/CPAP, CCP110, CEP135 and gamma-tubulin. When overexpressed, it is able to induce centrosome amplification through the simultaneous generation of multiple procentrioles adjoining each parental centriole during S phase. Phosphorylates 'Ser-151' of FBXW5 during the G1/S transition, leading to inhibit FBXW5 ability to ubiquitinate SASS6. Its central role in centriole replication suggests a possible role in tumorigenesis, centrosome aberrations being frequently observed in tumors. Also involved in trophoblast differentiation by phosphorylating HAND1, leading to disrupt the interaction between HAND1 and MDFIC and activate HAND1. Phosphorylates CDC25C and CHEK2.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedPLK4 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. Discovery of RP-1664: A First-in-Class Orally Bioavailable, Selective PLK4 Inhibitor.,Vallee F, Casas-Selves M, Bubenik M, Duplessis M, Sow B, Suarez C, Sangiorgi B, Li L, Hyer M, Papp R, Leclaire ME, Perryman AL, Liu B, Surprenant S, Mochirian P, Pau V, Maderova Z, Mader P, Yin SY, Goodfellow E, Roulston A, Stocco R, Godbout C, Baruah P, Bonneau-Fortin A, Schonhoft JD, Nejad P, Norman D, Truong VL, Crane S, Attia MA, Mao D, Sicheri F, Marshall CG, Zimmermann M, Bendahan D, Gallant M, Black WC J Med Chem. 2025 May 16. doi: 10.1021/acs.jmedchem.5c00529. PMID:40378279[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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