2. Academic Validation
  3. Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4

Discovery of Potent, Selective and Efficacious Aminopyrazole Inhibitors of PLK4

  • J Med Chem. 2025 Dec 11;68(23):25198-25212. doi: 10.1021/acs.jmedchem.5c02200.
Joon Won Jeong 1,  Trevor Chang 1,  Jeremy M Murray 1,  Ryan L Gonciarz 1,  Justin M Salvant 1,  Andre H St Amant 1,  Sanjay Bhattarai 1,  Jae H Chang 1,  Jo-Ting Chang 1,  Dana M Gwinn 1,  Christopher Kochansky 1,  Rhea Matsuura 1,  Leo Mok 1,  Nina M Muñoz 1,  Andrew G Raub 1,  David Shaya 1,  Ziqiang Wang 1,  Wei Xu 1,  Kai S Yang 1,  Heather J Finlay 1,  Brian A Sherer 1
Affiliations

Affiliation

  • 1 Small Molecule Discovery, Exelixis, Inc., 1851 Harbor Bay Parkway, Alameda, California 94502, United States.
PMID: 41329867 DOI: 10.1021/acs.jmedchem.5c02200
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 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z