title: SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples.
abstract: OBJECTIVE
  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.
authors.affiliation: Sunesis Pharmaceuticals Inc, South San Francisco, CA 94080, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Conroy
authors.forename: David E
authors.initials: DE
authors.lastname: Stockett
authors.forename: Duncan
authors.initials: D
authors.lastname: Walker
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.forename: Judith A
authors.initials: JA
authors.lastname: Fox
authors.forename: Rachael Elizabeth
authors.initials: RE
authors.lastname: Hawtin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases