Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models

Cancer Sci. 2019 Apr;110(4):1420-1430. doi: 10.1111/cas.13957. Epub 2019 Feb 26.


Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB-positive tumor cells in vitro, and exclusively induced G1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780-phosphorylated RB protein. Compared with the well-known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2-targeting antibody in ER-positive and HER2-positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER-positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.

Keywords: CDK 4/6; SHR6390; breast cancer; drug resistance; palbociclib.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Biomarkers, Tumor
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Mice
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Protein Kinase Inhibitors / pharmacology*
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6