Abstract 2758: Development of small molecule Bax agonists for lung cancer treatment

Abstract

Abstract Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently discovered that the serine(S) 184 site on Bax is a critical functional switch for controlling the proapoptotic activity of Bax. The structural pocket around the S184 residue holds great promise as an ideal target for small molecule docking. We therefore employed the S184 residue as a docking site for screening small molecule therapeutic agents using the UCSF DOCK program suite and the NCI library of small molecules. Three compounds named small molecule Bax agonists (i.e. SMBA1, SMBA2 and SMBA3) were found to induce a conformational change of Bax by blocking phosphorylation of its S184 site, facilitating Bax insertion into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis in human lung cancer cells. Intriguingly, SMBA1 potently suppresses lung tumor growth via apoptosis in vivo without significant normal tissue toxicity. Survival outcomes remain very poor for lung cancer patients due to resistance to standard therapeutic interventions with radiation and systemic chemotherapy. Development of novel Bax agonists as an entirely new class of anti-cancer drugs has translational value to foster novel strategies for the treatment of lung cancer and other Bax expressing malignancies. Citation Format: Meiguo Xin, Rui Li, Dongkyoo Park, Taofeek K. Owonikoko, Gabriel L. Sica, Patrick E. Corsino, Jia Zhou, Chunyong Ding, Andrew T. Magis, Suresh S. Ramalingam, Walter J. Curran, Fadlo R. Khuri, Xingming Deng. Development of small molecule Bax agonists for lung cancer treatment. [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 2758. doi:10.1158/1538-7445.AM2014-2758