Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold

Li, Zhengnian, Ishida, Ryosuke, Liu, Yan, Wang, Jinhua, Li, Yina, Gao, Yang, Jiang, Jie, Che, Jianwei, Sheltzer, Jason M, Robers, Matthew B, Zhang, Tinghu, Westover, Kenneth D, Nabet, Behnam, Gray, Nathanael S (May 2022) Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold. European Journal of Medicinal Chemistry, 238. p. 114433. ISSN 0223-5234

URL: https://www.ncbi.nlm.nih.gov/pubmed/35597007
DOI: 10.1016/j.ejmech.2022.114433

Abstract

Cyclin-dependent kinases (CDK) are attractive targets for drug discovery due to their wide range of cellular functions. CDK11 is an understudied CDK with roles in transcription and splicing, cell cycle regulation, neuronal function, and apoptosis. In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor. Employing a promising but nonselective CDK11-targeting scaffold (JWD-047), extensive structure-guided medicinal chemistry modifications led to the identification of ZNL-05-044. A combination of biochemical evaluations and NanoBRET cellular assays for target engagement guided the SAR towards a 2,4-diaminothiazoles CDK11 probe with significantly improved kinome-wide selectivity over JWD-047. CDK11 inhibition with ZNL-05-044 leads to G2/M cell cycle arrest, consistent with prior work evaluating OTS964, and impacts CDK11-dependent mRNA splicing in cells. Together, ZNL-05-044 serves as a tool compound for further optimization and interrogation of the consequences of CDK11 inhibition.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
CSHL Authors:
Communities: CSHL labs > Sheltzer lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 8 May 2022
Date Deposited: 26 May 2022 18:07
Last Modified: 26 May 2022 18:07
URI: https://repository.cshl.edu/id/eprint/40642

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