SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples

Cancer Chemother Pharmacol. 2009 Sep;64(4):723-32. doi: 10.1007/s00280-008-0921-5. Epub 2009 Jan 24.


Purpose: SNS-032 (formerly BMS-387032) is a potent, selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9, currently in phase 1 clinical trial for chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We used the MM cell line RPMI-8226 to evaluate the relationship between duration of SNS-032 exposure, target modulation of CDKs 2, 7 and 9, and induction of apoptosis. We also assessed target modulation in patient peripheral blood mononuclear cells (PBMCs) from phase 1 solid tumor patients treated with SNS-032.

Methods: Proliferation and colony forming assays were used to evaluate cytotoxicity, Western blot analyses to evaluate target modulation, FACS analysis to assess cell cycle distribution, RT-PCR to evaluate transcriptional inhibition.

Results: SNS-032 blocks the cell cycle via inhibition of CDKs 2 and 7, and transcription via inhibition of CDKs 7 and 9. Treatment of RPMI-8226 MM cells at 300 nM (IC(90)) for 6 h was sufficient for commitment to apoptosis. This correlated with inhibition of CDKs 2, 7 and 9, as reflected in substrate signaling molecules. SNS-032 activity was unaffected by human serum. Target modulation was observed in PBMC from treated patients.

Conclusions: These results demonstrate SNS-032 target modulation of CDKs 2, 7 and 9, and establish 6 h exposure as sufficient to commit RPMI-8226 MM cells to apoptosis. Combined with the demonstration of target modulation in PBMC from phase 1 solid tumor patients treated with SNS-032, these data support the ongoing clinical study of SNS-032 in MM and CLL.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / enzymology
  • Oxazoles / pharmacology*
  • Oxazoles / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use


  • Antineoplastic Agents
  • N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
  • Oxazoles
  • Protein Kinase Inhibitors
  • Thiazoles
  • Cyclin-Dependent Kinases