Abstract LB-310: Small molecule inhibitors of IKBKE with antitumor activity in cancer cells overexpressing IKBKE .

Abstract The serine/threonine kinase IKBKE is frequently overexpressed/activated in human cancer. Ectopic expression of IKBKE induces malignant transformation, cell migration, invasion and chemoresistance. Thus, IKBKE is a new attractive target for anti-cancer drug discovery. By screening of NCI Diversity Set and Clinical Collection I and II compound libraries using cell-based assay, we identified several IKBKE inhibitors, 3 of which directly inhibited IKBKE kinase activity in vitro and in vivo and the others only reduced phospho-IKBKE in vivo. One of the inhibitors, MCCK1, was further characterized and was found to directly bind to IKBKE. It inhibits IKBKE kinase as well as its downstream targets such as IkappaB, p65 and IRF3. MCCK1 is selective for IKBKE with moderate effect on TBK1 but does not inhibit the activation of IKKalpha/beta, STAT3, Erk-1/2, p38 or JNK. The inhibition of IKBKE by MCCK1 results in induction of cell growth arrest and apoptosis selectively in human cancer cells that harbor aberrant expression IKBKE. Further, MCCK1 inhibits tumor growth in nude mice of human cancer cells in which IKBKE is elevated but not of those cancer cells in which it is not. These data indicate that MCCK1 is an IKBKE inhibitor with anti-tumor activity in vitro and in vivo and could be a potential anti-cancer agent for patients whose tumors express elevated IKBKE. Citation Format: Yu Xin, Jianping Guo, Jin Q. Small molecule inhibitors of IKBKE with antitumor activity in cancer cells overexpressing IKBKE . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-310. doi:10.1158/1538-7445.AM2013-LB-310