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

Zhengnian Li; Ryosuke Ishida; Yan Liu; Jinhua Wang; Yina Li; Yang Gao; Jie Jiang; Jianwei Che; Jason M Sheltzer; Matthew B Robers; Tinghu Zhang; Kenneth D Westover; Behnam Nabet; Nathanael S Gray

doi:10.1016/j.ejmech.2022.114433

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

Eur J Med Chem. 2022 Aug 5:238:114433. doi: 10.1016/j.ejmech.2022.114433. Epub 2022 May 8.

Authors

Affiliations

¹ Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA, USA.
² Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA; Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
³ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
⁴ Yale University School of Medicine, New Haven, CT, USA.
⁵ Promega Corporation, Madison, WI, USA.
⁶ Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: bnabet@fredhutch.org.
⁷ Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA, USA. Electronic address: nsgray01@stanford.edu.

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.

Keywords: CDK11; Kinase inhibitor; Serine/threonine protein kinase; Structure-activity relationship.

MeSH terms

Apoptosis*
Cell Cycle Checkpoints
Cyclin-Dependent Kinase 2 / metabolism
Cyclin-Dependent Kinases* / metabolism
Structure-Activity Relationship

Substances

Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases

Grants and funding

K22 CA258805/CA/NCI NIH HHS/United States