Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 4, pp 723–732

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

  • Andrew Conroy
  • David E. Stockett
  • Duncan Walker
  • Michelle R. Arkin
  • Ute Hoch
  • Judith A. Fox
  • Rachael Elizabeth Hawtin
Original Article

DOI: 10.1007/s00280-008-0921-5

Cite this article as:
Conroy, A., Stockett, D.E., Walker, D. et al. Cancer Chemother Pharmacol (2009) 64: 723. doi:10.1007/s00280-008-0921-5

Abstract

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 (IC90) 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.

Keywords

SNS-032 Chronic lymphocytic leukemia Multiple myeloma Cyclin-dependent kinase Transcription Survival factors 

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Andrew Conroy
    • 1
  • David E. Stockett
    • 1
  • Duncan Walker
    • 2
  • Michelle R. Arkin
    • 3
  • Ute Hoch
    • 4
  • Judith A. Fox
    • 1
  • Rachael Elizabeth Hawtin
    • 1
  1. 1.Sunesis Pharmaceuticals, Inc.South San FranciscoUSA
  2. 2.Array BioPharmaBoulderUSA
  3. 3.Small Molecule Discovery CenterUniversity of CaliforniaSan FranciscoUSA
  4. 4.Nektar TherapeuticsSan CarlosUSA

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