Design, synthesis, and biological evaluation of novel 4,4'-bipyridine derivatives acting as CDK9-Cyclin T1 protein-protein interaction inhibitors against triple-negative breast cancer.

Abstract

Cyclin-dependent kinase 9 (CDK9) is directly related to tumor development in triple-negative breast cancer (TNBC) patients. Increased CDK9 is significantly associated with poor patient prognosis, while inhibiting CDK9-Cyclin T1 protein-protein interaction has recently been demonstrated as a new approach to TNBC treatment. Herein, we synthesized a novel class of 4,4'-bipyridine derivatives as potential CDK9-Cyclin T1 PPI inhibitors against TNBC. The represented compound B19 was found to be an excellent and selective CDK9-Cyclin T1 PPI inhibitor with good potency against TNBC cell lines while exhibiting lower toxicity in normal human cell lines than the positive compound I-CDK9. Notably, compound B19 showed good pharmacokinetic properties and excellent antitumor activity against TNBC (4T1) allografts in mice with a therapeutic index of more than 42 (TGI4T1(12.5 mg/kg,i.p.) = 63.1% vs. LD50 = 537 mg/kg). Moreover, the administration of B19 in combination with the PARP inhibitor Olaparib results in a significant increase of the antitumor activity in MDA-MB-231 cells relative to that of either single agent. To our knowledge, B19 is the first reported non-metal organic compound that acts as a selective CDK9-Cyclin T1 PPI inhibitor with in vivo antitumor activity, and it may be alone and in combination with PARP inhibitor Olaparib for TNBC therapy.

• Authors: Guiping Gao, Jiayi Li, Yin Cao, Xudan Li, Yuqing Qian, Xiumei Wang, Mengyu Li, Yingkun Qiu, Tong Wu, Liqiang Wang, Meijuan Fang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 261 Pg. 115858 (Dec 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 37837671 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Chemical References

• 4,4'-bipyridyl
• Cyclin T
• Poly(ADP-ribose) Polymerase Inhibitors
• Antineoplastic Agents
• Protein Kinase Inhibitors
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• Humans
• Mice
• Animals
• Triple Negative Breast Neoplasms (pathology)
• Cyclin T
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Cell Proliferation
• Antineoplastic Agents (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 9 (metabolism)