SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples
SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples
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DOI：
10.1007/s00280-008-0921-5
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发表时间：
2009-09-01
影响因子：
3
通讯作者：
Hawtin, Rachael Elizabeth
中科院分区：
文献类型：
--
作者：
Conroy, Andrew;Stockett, David E.;Hawtin, Rachael Elizabeth
SNS-032（以前称为BMS-387032）是一种有效的细胞周期蛋白依赖性激酶（CDK）2、7和9的选择性抑制剂，目前正在进行慢性淋巴细胞白血病（CLL）和多发性骨髓瘤（MM）的I期临床试验。我们使用MM细胞系RPMI-8226来评估SNS-032暴露的持续时间、CDK 2、7和9的靶向调节与细胞凋亡诱导之间的关系。我们还评估了SNS-032治疗的I期实体瘤患者的患者外周血单核细胞（PBMC）中的靶向调节。增殖和集落形成测定用于评估细胞毒性，Western印迹分析用于评估靶向调节，FACS分析用于评估细胞周期分布，RT-PCR用于评估转录抑制。SNS-032通过抑制CDK 2和7阻断细胞周期，以及通过抑制CDK 7和9的转录。以300 nM（IC 90）处理RPMI-8226 MM细胞6 h足以使细胞凋亡。这与CDK 2、7和9的抑制相关，如底物信号传导分子所反映的。SNS-032活性不受人血清的影响。这些结果证明SNS-032靶向调节CDK 2、7和9，并建立6小时暴露足以使RPMI-8226 MM细胞凋亡。结合来自用SNS-032治疗的I期实体瘤患者的PBMC中的靶向调节的证明，这些数据支持SNS-032在MM和CLL中的正在进行的临床研究。
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.