Abstract 5344: Novel thioxodihydroquinazolinone small molecules for combination with platinum drugs to reverse platinum resistance through inducing mitochondrial apoptosis independent of Bax and Bak

Abstract

Abstract Platinum drugs are among the most effective anticancer drugs against various types of cancers, and the effective treatment of tumors resistant to platinum drugs-based anticancer therapies (either intrinsic or acquired during treatment) is a critical challenge in the current clinic. Bax and Bak, which are the proapoptotic Bcl-2 family proteins, are essential for cisplatin-induced apoptosis. Unfortunately, Bax and its upstream apoptotic signaling pathways are often altered in cancer cells. Strategies that induce apoptosis bypassing Bax- and Bak-dependent pathway will thus provide new opportunities to overcome platinum drug resistance. We have identified the thioxodihydroquinazolinone, mdivi-1, as a member of a novel class of small molecules that when combined with cisplatin are able to induce Bax- and Bak-independent mitochondrial outer membrane permeabilization and subsequent apoptosis in platinum resistant tumor cells. In order to identify the pharmacophore that is minimally required for enhancing the efficacy of platinum drugs and bax/bak-independent mitochondrial apoptosis, we performed a structure activity relationship (SAR) study of a computationally selected library of mdivi-1 related small molecules through substructure and similarity searches in the small molecule library collection of the University of Pittsburgh Center for Chemical Methodologies and Library Development (UPCMLD). We were able to identify that a thiourea function is necessary but not sufficient for the synergism of this class of thioxodihydroquinazolinones with cisplatin. We have also identified more potent mdivi-1 analogs through this SAR study. These more potent novel thioxodihydroquinazolinone small molecules, when combined with cisplatin, induce a synergistic increase of replication stress and DNA damage, upregulation of a pro-apoptotic Bcl-2 family protein Noxa, and substantial mitochondrial dysfunction including mitochondrial uncoupling. Importantly, the combination of these thioxodihydroquinazolinones with cisplatin leads to efficient apoptosis in cells depleted of Bax and Bak. Taken together, we were able to establish a preliminary pharmacophore model of this class of thioxodihydroquinazolinones and identify more potent structures that are essential for guiding future compound optimization for preclinical studies. Given the essential roles of Bax and Bak in many different classes of chemotherapeutic and targeted therapeutic drugs, our thioxodihydroquinazolinone / platinum based combination approach provides a novel targeting strategy for a broad spectrum of drug resistant tumors. Citation Format: Wei Qian, Joseph Salamoun, Jingnan Wang, Vera Roginskaya, Bennett Van Houten, Peter Wipf. Novel thioxodihydroquinazolinone small molecules for combination with platinum drugs to reverse platinum resistance through inducing mitochondrial apoptosis independent of Bax and Bak. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5344. doi:10.1158/1538-7445.AM2015-5344