Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor

Bioorg Med Chem Lett. 2024 Jul 15:107:129769. doi: 10.1016/j.bmcl.2024.129769. Epub 2024 Apr 24.

Abstract

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).

Keywords: Breast cancer; CDK4 biased inhibitor; CDK4/6 inhibitor; In vitro and in vivo profilin.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation* / drug effects
  • Cyclin-Dependent Kinase 4* / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4* / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • Cyclin-Dependent Kinase 4
  • Protein Kinase Inhibitors
  • CDK4 protein, human
  • Antineoplastic Agents
  • Pyrimidines

Associated data

  • ClinicalTrials.gov/NCT05365178
  • ClinicalTrials.gov/NCT05375461