We recently characterized a novel camptothecin analog FL118. Interestingly, different from the two clinically used camptothecin analogs irinotecan and topotecan, which are topoisomerase 1 (Top1) inhibitors, FL118 appears to be a poor Top1 inhibitor at its therapeutic dose range. Instead, FL118 selectively inhibits multiple cancer survival and proliferation-associated antiapoptotic proteins including survivin, Mcl-1, XIAP, and cIAP2. We have demonstrated that genetic knockdown or overexpression of survivin, Mcl-1, XIAP, or cIAP2 modulates FL118's ability to inhibit cancer cell growth and induce apoptosis. FL118 is able to eliminate both small and large human tumor xenografts in animal models. Importantly, FL118 effectively overcomes topotecan treatment-induced resistance of human colon tumor in animal models. Pharmacokinetics (PK) studies indicated that FL118 prefers to be accumulated in tumor and rapidly cleared in blood stream in animal models. Furthermore, our most recent studies demonstrated that maintenance of a free hydroxyl group in the lactone ring of FL118 is critical for its antitumor activity, and the superior antitumor efficacy of FL118 heavily depends on its steric configuration (Zhao et al., Molecular Pharmaceutics). Based on the current observation of FL118 properties, we hypothesize that FL118 is an ideal lead for development of novel analogs that may possess distinct antitumor selectivity to overcome different treatment resistance. In this regard, we tested 146 new camptothecin analogs, which were synthesized based on either the FL118 core structure or the camptothecin core structure, in four cancer cell lines and two normal cell lines. We identified 19 top candidates that showed inhibition of cancer cell growth and induction of apoptosis that are better than or comparable to FL118. Intriguingly, all of the 19 top compounds possess the FL118 core structure. Further investigation of the 19 compounds using cancer cells with distinct treatment resistant backgrounds indicated that these compounds showed distinct antitumor selectivity among different treatment resistant cancer cells. Therefore, while our finding would need further investigation using in vivo human tumor animal models, we propose to develop a series of FL118 analogs for personalized cancer treatment to overcome different treatment resistance.
Citation Format: Fengzhi Li, Xiang Ling, David Westover, Xiaojun Liu, Chunyang Jin, Mansukh Wani. The novel camptothecin analog and antiapoptotic protein inhibitor FL118 appears to be a great backbone platform for development of personalized anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1627. doi:10.1158/1538-7445.AM2014-1627