SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples
- Andrew ConroyAffiliated withSunesis Pharmaceuticals, Inc.
- , David E. StockettAffiliated withSunesis Pharmaceuticals, Inc.
- , Duncan WalkerAffiliated withArray BioPharma
- , Michelle R. ArkinAffiliated withSmall Molecule Discovery Center, University of California
- , Ute HochAffiliated withNektar Therapeutics
- , Judith A. FoxAffiliated withSunesis Pharmaceuticals, Inc.
- , Rachael Elizabeth HawtinAffiliated withSunesis Pharmaceuticals, Inc. Email author
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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.
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.
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.
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.
KeywordsSNS-032 Chronic lymphocytic leukemia Multiple myeloma Cyclin-dependent kinase Transcription Survival factors
- SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples
Cancer Chemotherapy and Pharmacology
Volume 64, Issue 4 , pp 723-732
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- Chronic lymphocytic leukemia
- Multiple myeloma
- Cyclin-dependent kinase
- Survival factors
- Industry Sectors
- Author Affiliations
- 1. Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA, 94080, USA
- 2. Array BioPharma, Boulder, CO, 80301, USA
- 3. Small Molecule Discovery Center, University of California, San Francisco, CA, 94143, USA
- 4. Nektar Therapeutics, San Carlos, CA, 94070, USA