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

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 (TGI^4T1_{(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.