BS181 - CAS 1092443-52-1
Catalog number: 1092443-52-1
Category: Inhibitor
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Molecular Formula:
C22H32N6
Molecular Weight:
380.53
COA:
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Targets:
CDK
Description:
BS-181 is a highly selective CDK inhibitor for CDK7 with an IC(50) of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 micromol/L, with CDK2 being inhibited 35-fold less potently (IC(50) 880 nmol/L) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis to inhibit the growth of cancer cell lines, and showed antitumor effects in vivo. The drug was stable in vivo with a plasma elimination half-life in mice of 405 minutes after i.p. administration of 10 mg/kg. The same dose of drug inhibited the growth of MCF-7 human xenografts in nude mice. BS-181 therefore provides the first example of a potent and selective CDK7 inhibitor with potential as an anticancer agent.
Synonyms:
BS-181; BS181; BS 181
MSDS:
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InChIKey:
DNYBIOICMDTDAP-UHFFFAOYSA-N
InChI:
InChI=1S/C22H32N6/c1-17(2)19-16-26-28-21(25-15-18-10-6-5-7-11-18)14-20(27-22(19)28)24-13-9-4-3-8-12-23/h5-7,10-11,14,16-17,25H,3-4,8-9,12-13,15,23H2,1-2H3,(H,24,27)
Canonical SMILES:
CC(C)C1=C2N=C(C=C(N2N=C1)NCC3=CC=CC=C3)NCCCCCCN
Current Developer:
Imperial College London
1.The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.
Ali S;Heathcote DA;Kroll SH;Jogalekar AS;Scheiper B;Patel H;Brackow J;Siwicka A;Fuchter MJ;Periyasamy M;Tolhurst RS;Kanneganti SK;Snyder JP;Liotta DC;Aboagye EO;Barrett AG;Coombes RC Cancer Res. 2009 Aug 1;69(15):6208-15. doi: 10.1158/0008-5472.CAN-09-0301. Epub 2009 Jul 28.
Normal progression through the cell cycle requires the sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4, and CDK6. Direct or indirect deregulation of CDK activity is a feature of almost all cancers and has led to the development of CDK inhibitors as anticancer agents. The CDK-activating kinase (CAK) plays a critical role in regulating cell cycle by mediating the activating phosphorylation of CDK1, CDK2, CDK4, and CDK6. As such, CDK7, which also regulates transcription as part of the TFIIH basal transcription factor, is an attractive target for the development of anticancer drugs. Computer modeling of the CDK7 structure was used to design potential potent CDK7 inhibitors. Here, we show that a pyrazolo[1,5-a]pyrimidine-derived compound, BS-181, inhibited CAK activity with an IC(50) of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 micromol/L, with CDK2 being inhibited 35-fold less potently (IC(50) 880 nmol/L) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis to inhibit the growth of cancer cell lines, and showed antitumor effects in vivo.
2.Triptolide Induces Cell Killing in Multidrug-Resistant Tumor Cells via CDK7/RPB1 Rather than XPB or p44.
Yi JM;Huan XJ;Song SS;Zhou H;Wang YQ;Miao ZH Mol Cancer Ther. 2016 Jul;15(7):1495-503. doi: 10.1158/1535-7163.MCT-15-0753. Epub 2016 Mar 29.
Multidrug resistance (MDR) is a major cause of tumor treatment failure; therefore, drugs that can avoid this outcome are urgently needed. We studied triptolide, which directly kills MDR tumor cells with a high potency and a broad spectrum of cell death. Triptolide did not inhibit P-glycoprotein (P-gp) drug efflux and reduced P-gp and MDR1 mRNA resulting from transcription inhibition. Transcription factors including c-MYC, SOX-2, OCT-4, and NANOG were not correlated with triptolide-induced cell killing, but RPB1, the largest subunit of RNA polymerase II, was critical in mediating triptolide's inhibition of MDR cells. Triptolide elicited antitumor and anti-MDR activity through a universal mechanism: by activating CDK7 by phosphorylating Thr170 in both parental and MDR cell lines and in SK-OV-3 cells. The CDK7-selective inhibitor BS-181 partially rescued cell killing induced by 72-hour treatment of triptolide, which may be due to partial rescue of RPB1 degradation. We suggest that a precise phosphorylation site on RPB1 (Ser1878) was phosphorylated by CDK7 in response to triptolide. In addition, XPB and p44, two transcription factor TFIIH subunits, did not contribute to triptolide-driven RPB1 degradation and cell killing, although XPB was reported to covalently bind to triptolide.
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CAS 1092443-52-1 BS181

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