The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.

Content Provider	Semantic Scholar
Author	Ali, Simak Heathcote, Dean A. Kroll, Sebastian Herbert Benjamin Jogalekar, Ashutosh S. Scheiper, Bodo Patel, Hetal Chimanbhai Brackow, Jan Siwicka, Alekasandra Fuchter, Matthew J. Periyasamy, Manikandan Tolhurst, Robert S. Kanneganti, Seshu K. Snyder, James P. Liotta, Dennis C. Aboagye, Eric O. Barrett, Anthony G. M. Coombes, Raul Charles
Copyright Year	2009
Abstract	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. 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.
Starting Page	3
Ending Page	4
Page Count	2
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://cancerres.aacrjournals.org/content/canres/69/15/6208.full.pdf
PubMed reference number	19638587v1
Alternate Webpage(s)	https://doi.org/10.1158/0008-5472.CAN-09-0301
DOI	10.1158/0008-5472.can-09-0301
Journal	Cancer research
Volume Number	69
Issue Number	15
Language	English
Access Restriction	Open
Subject Keyword	Antineoplastic Agents Apoptosis BS-181 CDC2 Protein Kinase CDK2 gene CDK2 protein, human CDK6 protein, human CDK7 gene Cell Cycle Arrest Cultured Cell Line Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Cyclins Deregulation Excretory function Malignant Neoplasms Mice, Nude TRANSCRIPTION FACTOR Transcription Factors, General Xenograft procedure cancer cell cyclin-dependent protein kinase activity
Content Type	Text
Resource Type	Article