生物活性

• 靶点

  CDK2 IC50:38nM

  Cdk7 IC50:62nM

  Cdk9 IC50:4nM

• 描述The CDKs (cyclin dependent kinases), as direct regulators of specific phases of the cell cycle, can control cellular proliferation and transcription with their activating cyclin partners and subunit inhibitors. Thus, the molecular events that distinguish the activities of CDKs can be leveraged as pharmacodynamics biomarkers for activity of the CDKs. For example, CDK2 inhibition can be assessed by increased level of cyclin E, decreased level of Cdc6 or phosphorylation of Rb. Decreased phosphorylation of pSer5 and pSer2 of RNA pol II CTD would indicate inhibition of CDKs 7 and 9, respectively. SNS-032 (BMS-387032) is a selective inhibitor of CDK2/Cyclin A, CDK2/Cyclin E, CDK7/Cyclin H and CDK9/Cyclin T with IC50 values of 38, 48, 62 and 4 nM (measured by enzymatic activity assay), respectively, with modest inhibitory activity against CDK5/p35, CDK1/Cyclin B and CDK4/Cyclin D with IC50 values of 340, 480 and 925 nM. After exposure to 0.03 - 3 μM SNS-032, stabilization of cyclin E can be observed by 4h and persisted for at least 2h post-washout of SNS-032 in RPMI-8226 cells, accompanied with decrease in Cdc6 at 4h. Cellular IC50 values of 231 nM and 192 nM for SNS-032 for 16h were identified for inhibition of CDK7 and CDK9, which was read out by phosphorylation of Ser5 and Ser2 of RNA Pol II CTD, in RPMI-8226 MM cells. 300 nM SNS-032 for up to 6h showed both decrease of pSer2 RNA Pol II-CTD and increase in cleaved PARP. Treatment with 300 nM SNS-032 for 24h caused arrested cell cycle progression at G2/M in asynchronous HCT116 cells^[1]. Exposure with 0.3 μM SNS-032 for 6 hours can significant decrease the mRNA and protein level of Mcl-1 and XIAP, the antiapoptotic proteins, in CLL cells from the same set of 6 patients^[2]. Treatment with 15 mg/kg SNS-032 intraperitoneally every 2 days for about 2 weeks can inhibit the growth of xenografts, BaF3-T674I FIP1L1-PDGFRα or KBM5-T315I cells, in nude mice^[3]. Up to now, a phase 1 study of SNS-032 treatment for B-lymphoid malignancies, chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma has been completed (see in https://www.clinicaltrials.gov/).
• 作用机制SNS-032 can compete with ATP-binding pocket to CDK7 and 9.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human A2780 cell line	-	Proliferation assay	72 h	Antiproliferative effect against human A2780 cell line was determined in a whole cell 72 hr cytotoxicity assay, IC50=95 nM	15027863
  human HCT116 cells	-	Function assay	-	Inhibition of CDK9 in human HCT116 cells assessed as phosphor-ser2 level of RNA polymerase 2 after 16 hrs by high content cellular assay, IC50=458 nM	18842409
  human HCT116 cells	-	Function assay	16 h	Inhibition of CDK9-mediated RNA pol 2 phosphorylation at ser2 in human HCT116 cells after 16 hrs by HCS assay, IC50=0.55 μM	18926699

• 动物研究
  剂量	Mice[4] (i.p.): min = 18 mg/kg, max = 48 mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[4] Rats[4] Dogs[4] Dose 24 μmol/kg 24 μmol/kg 1.2 μmol/kg Administration i.v. / p.o. i.v. / p.o. i.v. / p.o. Cmax 1.4 μM (p.o.) 0.52 μM (p.o.) 0.33 μM (p.o.) T1/2 4.8 h (i.v.) 5.3 h (i.v.) 7 h (i.v.) F 1 0.31 0.28 Tmax 2.0 h (p.o.) 4.7 h (p.o.) 0.4 h (p.o.) AUCtot 4.8 μM·h (i.v.) 6.3 μM·h (i.v.) 2.1 μM·h (i.v.) Vss 14 L/kg (i.v.) 15 L/kg (i.v.) 3.6 L/kg (i.v.) CL 81 ml/min/kg (i.v.) 64 ml/min/kg (i.v.) 9.4 ml/min/kg (i.v.) MRT 2.8 h (i.v.) 3.7 h (i.v.) 6.3 h (i.v.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00292864	Tumors	Phase 1	Completed	-	United States, Arizona ... more >> Premiere Oncology of Arizona Scottsdale, Arizona, United States, 85260 United States, California University of California Davis Medical Center Davis, California, United States, 95817 United States, Massachusetts Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02115 Beth Israel Deaconess Medical Center Boston, Massachusetts, United States, 02215 Massachusetts General Hospital Boston, Massachusetts, United States, 02215 United States, Pennsylvania Fox Chase Cancer Center Philadelphia, Pennsylvania, United States, 19111 Collapse <<
  NCT00446342	B-lymphoid Malignancies ... more >> Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Multiple Myeloma Collapse <<	Phase 1	Completed	-	United States, California ... more >> City of Hope Duarte, California, United States, 91010 Stanford Cancer Center Stanford, California, United States, 94305 United States, Georgia Winship Cancer Institute at Emory University Atlanta, Georgia, United States, 30322 United States, Maryland Greenebaum Cancer Center, University of Maryland Baltimore, Maryland, United States, 21201 United States, New Jersey Hackensack University Medical Center at the Cancer Center Hackensack, New Jersey, United States, 07601 United States, Texas MD Anderson Cancer Center, University of Texas Houston, Texas, United States, 77230 Collapse <<

• 参考文献

• [1] Conroy A, Stockett DE, 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. 2009 Sep;64(4):723-32.

  [2] Chen R, Wierda WG, et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2009 May 7;113(19):4637-45.

  [3] Wu Y, Chen C, et al. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells. Clin Cancer Res. 2012 Apr 1;18(7):1966-78.

  [4] Misra RN, Xiao HY, et al. N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem. 2004 Mar 25;47(7):1719-28.