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)

This is a non-PDB format compatible entry.

Summary for 9Y9B

• Entry DOI: 10.2210/pdb9y9b/pdb
• Descriptor: Serine/threonine-protein kinase PLK4, SULFATE ION, (1R,3r,5S)-3-hydroxy-N-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]-8-azabicyclo[3.2.1]octane-8-carboxamide, ... (4 entities in total)
• Functional Keywords: plk4, type 1 inhibitor, sbdd, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32133.08

Authors

Murray, J.M. (deposition date: 2025-09-13, release date: 2026-02-18)

Primary citation

Jeong, J.W.,Chang, T.,Murray, J.M.,Gonciarz, R.L.,Salvant, J.M.,St Amant, A.H.,Bhattarai, S.,Chang, J.H.,Chang, J.T.,Gwinn, D.M.,Kochansky, C.,Matsuura, R.,Mok, L.,Munoz, N.M.,Raub, A.G.,Shaya, D.,Wang, Z.,Xu, W.,Yang, K.S.,Finlay, H.J.,Sherer, B.A.
Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4.
J.Med.Chem., 68:25198-25212, 2025

PubMed Abstract: Polo-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 , 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 in a CHP-134 neuroblastoma xenograft tumor model.

PubMed: 41329867
DOI: 10.1021/acs.jmedchem.5c02200

Experimental method

X-RAY DIFFRACTION (2.7 Å)