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

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 (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: Andrew Conroy, David E Stockett, Duncan Walker, Michelle R Arkin, Ute Hoch, Judith A Fox, Rachael Elizabeth Hawtin
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 64 Issue 4 Pg. 723-32 (Sep 2009) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19169685 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

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

Topics

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