SNS-032 (BMS-387032)
(Synonyms: BMS-387032) 目录号 : GC11396
A Cdk2, Cdk7, and Cdk9 inhibitor
Cas No.:345627-80-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Chronic lymphocytic leukemia (CLL) cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
0.1, 0.3 and 1 μM; 6 or 24 hrs |
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Applications |
CLL cells treated with SNS-032 for 6 or 24 hrs showed a decrease in the phosphorylation of Ser2 and Ser5 of the CTD of RNA Pol II, which appeared to be both time- and concentration- dependent, and remarkably consistent among samples. For the phosphorylation of Ser2, the inhibition of SNS-032 was greater than that for the phosphorylation of Ser5, this was consistent with the fact that IC50 for the inhibition of CDK9 was lower compared with that for the inhibition of CDK7 (4 nM vs 62 nM). After 6 hrs of SNS-032 exposure, protein levels of CDK7 and CDK9 were stable, but declined at 24 hrs. |
| Animal experiment [2]: | |
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Animal models |
MDA-MB-435 xenograft mouse model |
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Dosage form |
15 mg/kg; i.p.; every 3 days for approximately one month |
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Applications |
In SNS-032-treated nude mice, the volume of the xenografted breast tumor was significantly inhibited by 65.77% after 30 days of drug administration (eight SNS-032 injections). |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood, 2009, 113(19):4637-4645. [2]. Xie G, Tang H, Wu S, Chen J, Liu J, Liao C. The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo. Int J Oncol. 2014 Aug;45(2):804-12. | |
SNS-032 (BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDKs) 2, 7, and 9 [1], with IC50 values of 38 nM, 62 nM and 4 nM, respectively [2].
CDKs mean a family of serine/threonine kinases regulating cell cycle process. Some CDKs are related to transcription control and are often perturbed in cancer cells [3].
Decrease in the phosphorylation at Ser5 and Ser2 in the C-terminal domain (CTD) of RNA Pol II can indicate the inhibition to CDK9 and CDK7 [1]. Chronic lymphocytic leukemia (CLL) cells treated with SNS-032 for 6 or 24 hours showed a decrease in the phosphorylation of Ser2 and Ser5 of the CTD of RNA Pol II, this appeared to be both time- and concentration- dependent, and remarkably consistent among samples. For the phosphorylation of Ser2, the inhibition of SNS-032 was greater than that for the phosphorylation of Ser5, this was consistent with the fact that IC50 for the inhibition of CDK9 was lower compared with that for the inhibition of CDK7 (4 nM vs 62 nM). After 6 hours of SNS-032 exposure, protein levels of CDK7 and CDK9 were stable, but declined at 24 hours [4].
In patients with chronic lymphocytic leukemia (CLL), infusion of SNS-032 in a total dose of 75 mg/m2 resulted in a decrease in the phosphorylation at Ser5 and Ser2 in the C-terminal domain of RNA Pol II. This indicated the inhibition to Cdk9 and Cdk7 by SNS-032. This inhibition was first seen 2 hours after the beginning of the infusion with SNS-032, was pronounced after 6 hours and returned to baseline after 24 hours [1].
References:
[1]. Tong W.G., Chen R., Plunkett W., et al. Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma. Journal of Clinical Oncology, 2010, 28(18):3015- 3022.
[2]. Chipumuro E., Marco E., Christensen C.L., et al. CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer. Cell, 2014, 159:1-14.
[3]. Meng H., Jin Y.M., Liu H., et al. SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt. Journal of Hematology & Oncology, 2013, 6:18.
[4]. Chen R., Wierda W.G., Chubb S., et al. Mechanism of action of SNS032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood, 2009, 113(19):4637-4645.
| Cas No. | 345627-80-7 | SDF | |
| 别名 | BMS-387032 | ||
| 化学名 | N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide | ||
| Canonical SMILES | CC(C)(C)C1=CN=C(O1)CSC2=CN=C(S2)NC(=O)C3CCNCC3 | ||
| 分子式 | C17H24N4O2S2 | 分子量 | 380.53 |
| 溶解度 | ≥ 19.05mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6279 mL | 13.1396 mL | 26.2791 mL |
| 5 mM | 0.5256 mL | 2.6279 mL | 5.2558 mL |
| 10 mM | 0.2628 mL | 1.314 mL | 2.6279 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Cyclin-dependent kinase 7/9 inhibitor SNS-032 induces apoptosis in diffuse large B-cell lymphoma cells
Approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory or relapse to standard chemotherapy, and most of them are activated B cell-like DLBCLs (ABC-DLBCL) and germinal center B cell-like DLBCLs (GCB-DLBCL). SNS-032, a novel and selective CDK7/9 inhibitor, that the first phase clinical trials approved by US FDA for cancer treatment have been completed. In this study, we investigated the anti-tumor effect of SNS-032 in ABC- and GCB-DLBCL subtypes. We report that SNS-032 induced growth inhibition and cell apoptosis in both DLBCL cells in vitro, and inhibited the growth of both DLBCL xenografts in nude mice. Mechanistically, SNS-032 inhibited RNA polymerase II, which led to transcriptional-dependent suppression of NF-κB signaling pathway and its downstream targets involved in cell survival; SNS-032 also downregulates BCL-2 and c-MYC in both mRNA and protein levels. Significantly, these findings provide pre-clinical evidence for application of targeting the CDK7/9 in DLBCL.
Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.
A phase 1 study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors
Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective was to assess the safety and tolerability of SNS-032 and to evaluate its bioavailability as an oral solution.
Methods: Patients with metastatic solid tumors or refractory lymphoma were treated with a starting dose of 4 mg/m2 intravenously administered over 1-h with a cycle defined as 3 weekly doses of SNS-032 every 21 days. Three patient cohorts were utilized in the dose-escalation schema. Pharmacokinetic studies were performed. For the 13 and 16 mg/m2 dose cohorts, the first dose of cycle 2 was given as an oral solution to estimate the oral bioavailability of the drug in humans.
Results: A total of 21 patients were enrolled. Twenty treated patients received a total of 39 cycles of treatment. The most common treatment-related adverse events occurring with greater than 20% incidence were fatigue (25%) and nausea (20%). Following intravenous administration, plasma concentrations declined in a biphasic manner, resulting in mean terminal half-lives between 5 and 10 hours. The mean Cmax and AUC0-inf increased nearly linearly with dose, ranging from 0.067 to 0.287 microg/ml and 0.103 to 0.553 microg h/ml, respectively. The CL and Vss remained unchanged with increasing dose levels, averaging 38 l/h/m2 and 212 l/m2, respectively. Average oral bioavailability was 19% (range: 4-33%). Three (15%) patients experienced a best response of stable disease. Study enrollment was terminated during dose-escalation due to a change in the development strategy for the study drug.
Conclusions: SNS-032 administered as a weekly 1-h infusion was well tolerated, although study enrollment was terminated during dose-escalation and the MTD of SNS-032 administered intravenously on days 1, 8, and 15 of each treatment cycle was not reached. Tumor progression or stable disease was determined to be the best response in all evaluable patients. At the dose levels tested, the oral bioavailability of SNS-032 ranged from 4-33%. The data suggest that oral administration of SNS-032 may be feasible, though the tolerability and bioavailability of the oral formulation would have to be formally assessed.
SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt
Background: Acute myeloid leukemia (AML) is a heterogeneous disorder with aberrant regulation of a variety of signal pathways. Therefore, simultaneous targeting of two or even more deregulated signal transduction pathways is needed to overcome drug resistance. Previously, it was reported that SNS-032, a selective cyclin-dependent kinase inhibitor, is an effective agent for treatment of AML; however, the molecular mechanisms of SNS-032-induced cell death of AML cells are not yet fully understood. The aim of the study was to characterize the effects in vitro of SNS-032, used alone and in combination with an Akt inhibitor perifosine, against AML cells and to identify the mechanism involved.
Results: SNS-032 significantly induced cytotoxicity in human AML cell lines and blasts from patients with newly diagnosed or relapsed AML. However, Kasumi-1 cells and some of leukemic samples (14.9%) from AML patients were resistant to SNS-032-mediated cell death. Western blot analysis showed that SNS-032 strongly inhibited the phosphorylation of mammalian target of rapamycin (mTOR) on Ser 2448 and Ser2481, and that removal of SNS-032 resulted in partial recovery of cell death and reactivation of phosphorylation of mTOR. Moreover, exogenous insulin-like growth factor-1 (IGF-1) did not reverse SNS-032-induced cell growth inhibition and downregualtion of phosphor-mTOR at Ser2448 and Ser2481 although slight suppression of IGF-1R expression was triggered by the agent. Furthermore, SNS-032 at a lower concentration (60-80 nM) enhanced AML cell cytotoxicity induced by perifosine, an Akt inhibitor. Importantly, SNS-032 treatment reduced colony formation ability of AML cells, which was significantly increased when two agents were combined. This combination therapy led to almost complete inhibition of Akt activity.
Conclusion: We conclude that SNS-032 might directly target mammalian target of rapamycin complex 1 (mTORC1)/mTORC2. Our results further provide a rationale for combining SNS-032 with perifosine for the treatment of AML.
Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma
Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.