SNS-032, BMS-387032A potent and selective Cdk inhibitor

SNS 032, BMS-387032

N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide

Cas 345627-80-7, MP 165-167° C

M.Wt:380.53, Formula:C₁₇H₂₄N₄O₂S₂

SNS 032, BMS-387032 HYDROCHLORIDE

A potent and selective Cdk inhibitor

Potent inhibitor of cyclin-dependent kinases (cdks) 9, 2 and 7 (IC₅₀ values are 4, 38 and 62 nM respectively). Displays no activity against 190 additional kinases (IC₅₀ >1000 nM). Arrests the cell cycle at G₂/M; inhibits transcription, proliferation and colony formation, and induces apoptosis in RPMI-8226 multiple myeloma cells. Prevents tumor cell-induced VEGF secretion and in vitro angiogenesis. SNS-032 (BMS-387032) has firstly been described as a selective inhibitor of CDK2 with IC50 of 48 nM in cell-free assays and is 10- and 20-fold selective over CDK1/CDK4. It is also found to be sensitive to CDK7/9 with IC50 of 62 nM/4 nM, with little effect on CDK6. Phase 1.

Quality Control & MSDS

COA NMR HPLC Datasheet SDS/MSDS

• COA (Certificate Of Analysis)
• HPLC
• NMR (Nuclear Magnetic Resonance)
• MSDS (Material Safety Data Sheet)

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].

SNS-032 (formerly BMS-387032) is a small-molecule cyclin-dependent kinase (CDK) inhibitor currently in phase I clinical trials for the treatment of B-cell malignancies and advanced solid tumors. Preclinical studies have shown that SNS-032 is a specific and potent inhibitor of CDK2, 7 and 9 which induces cell cycle arrest and apoptosis in tumor cell lines. It was shown to inhibit in vitro angiogenesis and prostaglandin E2 (PGE2) production, both strongly associated with tumorigenesis. Phase I clinical trials support the safety and tolerability of SNS-032 as evaluated in dose-escalation studies. The compound is currently administered by i.v. infusion but has shown promising potential for oral delivery.

NMR

CLIP

The structures of representative protein kinases inhibitors based on the aminopyrazole scaffold.http://www.mdpi.com/1422-0067/14/11/21805/htm

CLIP

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, 

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 {N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032}, has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC₅₀ = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC₅₀ = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5−7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a sc/ip A2780 human ovarian carcinoma xenograft model.

CLIP

http://pubs.rsc.org/en/content/articlehtml/2016/md/c6md90040b

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM).

COMPD 25

1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.21 (s, 1H), 8.74 (d, J = 0.9 Hz, 1H), 8.62 (dd, J = 8.2, 1.5 Hz, 1H), 8.56 (dd, J = 4.7, 1.5 Hz, 1H), 8.16-8.13 (m, 2H), 7.64 (br d, J = 8.6 Hz, 1H), 7.52-7.47 (m, 2H), 4.14 (t, J = 5.9 Hz, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.47-2.42 (m, 4H), 1.53-1.47 (m, 4H), 1.42 – 1.33 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 160.74, 158.32, 156.72, 154.88, 150.74, 146.47, 145.38, 143.74, 134.21, 125.02, 124.16, 122.29, 119.60, 114.32, 94.06, 66.49, 57.35, 54.35, 25.54, 23.88. HRMS (ESI+ ): calcd for C22H25N8O (M + H)+ , 417.2146; found 417.2163.

NOTE, THERE IS ERROR IN STRUCTURE ABOVE OF SNS 032

CC(C)(C)C1=CN=C(O1)CSC2=CN=C(S2)NC(=O)C3CCNCC3