@article{9b1ab0873e424becbdf671750d10fad7,
title = "Synthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold",
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",
author = "Zhengnian Li and Ryosuke Ishida and Yan Liu and Jinhua Wang and Yina Li and Yang Gao and Jie Jiang and Jianwei Che and Sheltzer, {Jason M.} and Robers, {Matthew B.} and Tinghu Zhang and Westover, {Kenneth D.} and Behnam Nabet and Gray, {Nathanael S.}",
note = "Funding Information: We thank members of the Westover, Nabet, and Gray laboratories and S. Nabet for helpful discussions. This work was supported by grants from American Cancer Society Award 132205-RSG-18-039-01-DMC (K.D.W.); Cancer Prevention and Research Institute of Texas RP170373 (K.D.W); Welch Foundation Grant I1829 (K.D.W.); NCI K22 CA258805 (B.N.); Fred Hutchinson Cancer Center start-up funds (B.N.). Funding Information: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.M.S. has received consulting fees from Ono Pharmaceuticals, Merck , and Omega Funds and is an advisor to Tyra Biosciences and Meliora Therapeutics. K.D.W is a member of the SAB for Vibliome Therapeutics. The Westover lab receives or has received research funding from Astellas and Revolution Medicines. N.S.G. is a Scientific Founder, member of the SAB and equity holder in C4 Therapeutics, Syros, Soltego (board member), B2S/Voronoi, Allorion, Lighthorse, Cobroventures, GSK , Larkspur (board member) and Matchpoint. The Gray lab receives research funding from Springworks and Interline. T.Z is scientific funder, equity holder and consultant in Matchpoint. J.C. is a scientific founder and equity holder of Matchpoint and M3 bioinformatics & technology Inc, and a consultant and equity holder to Soltego, Allorion, Matchpoint. Funding Information: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.M.S. has received consulting fees from Ono Pharmaceuticals, Merck, and Omega Funds and is an advisor to Tyra Biosciences and Meliora Therapeutics. K.D.W is a member of the SAB for Vibliome Therapeutics. The Westover lab receives or has received research funding from Astellas and Revolution Medicines. N.S.G. is a Scientific Founder, member of the SAB and equity holder in C4 Therapeutics, Syros, Soltego (board member), B2S/Voronoi, Allorion, Lighthorse, Cobroventures, GSK, Larkspur (board member) and Matchpoint. The Gray lab receives research funding from Springworks and Interline. T.Z is scientific funder, equity holder and consultant in Matchpoint. J.C. is a scientific founder and equity holder of Matchpoint and M3 bioinformatics & technology Inc, and a consultant and equity holder to Soltego, Allorion, Matchpoint.We thank members of the Westover, Nabet, and Gray laboratories and S. Nabet for helpful discussions. This work was supported by grants from American Cancer Society Award 132205-RSG-18-039-01-DMC (K.D.W.); Cancer Prevention and Research Institute of Texas RP170373 (K.D.W); Welch Foundation Grant I1829 (K.D.W.); NCI K22 CA258805 (B.N.); Fred Hutchinson Cancer Center start-up funds (B.N.). Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = aug,
day = "5",
doi = "10.1016/j.ejmech.2022.114433",
language = "English (US)",
volume = "238",
journal = "CHIM.THER.",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",
}