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Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2. | LitMetric

Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2.

Mol Cancer Ther

Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy.

Published: March 2007

AI Article Synopsis

  • VRX0466617 is a newly identified small-molecule inhibitor that specifically targets Chk2, a protein kinase involved in cellular responses to DNA damage.
  • The compound effectively blocks Chk2's enzymatic activity and activation from ionizing radiation, influencing specific phosphorylation sites without affecting others, showcasing its selectivity.
  • VRX0466617 demonstrates potential applications for studying Chk2 pathways, showing minimal impact on cell cycle distribution and no hindrance on the efficacy of certain anticancer drugs, while nonetheless reducing IR-induced cell death.

Article Abstract

VRX0466617 is a novel selective small-molecule inhibitor for Chk2 discovered through a protein kinase screening program. In this study, we provide a detailed biochemical and cellular characterization of VRX0466617. We show that VRX0466617 blocks the enzymatic activity of recombinant Chk2, as well as the ionizing radiation (IR)-induced activation of Chk2 from cells pretreated with the compound, at doses between 5 and 10 micromol/L. These doses of VRX0466617 inhibited, to some extent, the phosphorylation of Chk2 Ser(19) and Ser(33-35), but not of Chk2 Thr(68), which is phosphorylated by the upstream ataxia-telangiectasia mutated (ATM) kinase. Interestingly, VRX0466617 induced the phosphorylation of Chk2 Thr(68) even in the absence of DNA damage, arising from the block of its enzymatic activity. VRX0466617 prevented the IR-induced Chk2-dependent degradation of Hdmx, concordant with the in vivo inhibition of Chk2. Analysis of ATM/ATM and Rad3-related substrates Smc1, p53, and Chk1 excluded a cross-inhibition of these kinases. VRX0466617 did not modify the cell cycle phase distribution, although it caused an increase in multinucleated cells. Whereas VRX0466617 attenuated IR-induced apoptosis, in short-term assays it did not affect the cytotoxicity by the anticancer drugs doxorubicin, Taxol, and cisplatin. These results underscore the specificity of VRX0466617 for Chk2, both in vitro and in vivo, and support the use of this compound as a biological probe to study the Chk2-dependent pathways.

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Source
http://dx.doi.org/10.1158/1535-7163.MCT-06-0567DOI Listing

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