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Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2024 Sep; Vol. 150, pp. 107550. Date of Electronic Publication: 2024 Jun 10. - Publication Year :
- 2024
-
Abstract
- Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Ligands
Structure-Activity Relationship
Molecular Structure
Drug Screening Assays, Antitumor
Drug Discovery
Animals
HCT116 Cells
Cyclin-Dependent Kinase 9 antagonists & inhibitors
Cyclin-Dependent Kinase 9 metabolism
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Cell Proliferation drug effects
Drug Design
Antineoplastic Agents pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Dose-Response Relationship, Drug
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 150
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38878756
- Full Text :
- https://doi.org/10.1016/j.bioorg.2024.107550