TY - JOUR
T1 - Synthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold
AU - Li, Zhengnian
AU - Ishida, Ryosuke
AU - Liu, Yan
AU - Wang, Jinhua
AU - Li, Yina
AU - Gao, Yang
AU - Jiang, Jie
AU - Che, Jianwei
AU - Sheltzer, Jason M.
AU - Robers, Matthew B.
AU - Zhang, Tinghu
AU - Westover, Kenneth D.
AU - Nabet, Behnam
AU - Gray, Nathanael S.
N1 - Publisher Copyright:
© 2022
PY - 2022/8/5
Y1 - 2022/8/5
N2 - 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.
AB - 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.
KW - CDK11
KW - Kinase inhibitor
KW - Serine/threonine protein kinase
KW - Structure-activity relationship
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U2 - 10.1016/j.ejmech.2022.114433
DO - 10.1016/j.ejmech.2022.114433
M3 - Article
C2 - 35597007
AN - SCOPUS:85130585905
SN - 0223-5234
VL - 238
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114433
ER -