9y9b
PLK4 in complex with Compound 6 (3-hydroxy-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxamide)
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 PubMedPolo-like kinase 4 (PLK4) is a therapeutic target of high interest due to its essential role in mitotic regulation and centriole duplication. Recently, centriole depletion driven by PLK4 inhibition has been identified as a synthetically lethal target for cancers with elevated TRIM37 expression. Herein, we disclose the discovery of 25, a potent and selective PLK4 inhibitor. A validated hit from high-throughput screening of our compound library provided the starting point for further optimization. Structural analysis of multiple X-ray cocrystal structures enabled the design of analogs that demonstrated excellent kinome selectivity. Tumor regression was observed in efficacy studies of compound 25 in a CHP-134 neuroblastoma xenograft tumor model. Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4.,Jeong JW, Chang T, Murray JM, Gonciarz RL, Salvant JM, St Amant AH, Bhattarai S, Chang JH, Chang JT, Gwinn DM, Kochansky C, Matsuura R, Mok L, Munoz NM, Raub AG, Shaya D, Wang Z, Xu W, Yang KS, Finlay HJ, Sherer BA J Med Chem. 2025 Dec 11;68(23):25198-25212. doi: 10.1021/acs.jmedchem.5c02200. , Epub 2025 Dec 2. PMID:41329867[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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