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

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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.

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Acknowledgments

Samer Nuwayhid and Tai Wong for technical support. Bob McDowell for help with manuscript preparation. Patients who donated blood samples for correlative study analyses.

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Authors and Affiliations

  1. Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA, 94080, USA

    Andrew Conroy, David E. Stockett, Judith A. Fox & Rachael Elizabeth Hawtin

  2. Array BioPharma, Boulder, CO, 80301, USA

    Duncan Walker

  3. Small Molecule Discovery Center, University of California, San Francisco, CA, 94143, USA

    Michelle R. Arkin

  4. Nektar Therapeutics, San Carlos, CA, 94070, USA

    Ute Hoch

Authors
  1. Andrew Conroy
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  2. David E. Stockett
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  3. Duncan Walker
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  4. Michelle R. Arkin
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  5. Ute Hoch
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  6. Judith A. Fox
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  7. Rachael Elizabeth Hawtin
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Correspondence to Rachael Elizabeth Hawtin.

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Conroy, A., Stockett, D.E., Walker, D. et al. SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemother Pharmacol 64, 723–732 (2009). https://doi.org/10.1007/s00280-008-0921-5

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  • DOI: https://doi.org/10.1007/s00280-008-0921-5

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