Abstract 788: Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria

Abstract

Abstract The mitochondrial protein ANT2 is one of the four isoforms of the ADP/ATP translocase and is expressed in highly proliferating cells. ANT2 plays a crucial role in the maintenance of transmembrane potential and mitochondrial integrity in tumor cells by importing glycolytic ATP into the mitochondrial matrix. Thus, this protein is required for tumor cell survival and displays anti-apoptotic function. Recently, ANT2 upregulation was shown to be involved in drug resistance process in various cancer types. Considering ANT2 role in tumor cell metabolism, we searched for ANT2-ligand small molecules. Ligands were first identified by virtual screening of chemical library on 3D model of human ANT2 and validated as ADP/ATP translocase inhibitors using our screening platform on isolated mitochondria. Compound specificity for ANT2 isoform was validated by cellular knock-down and pull-down experiments. ANT2-ligands optimization lead to the selection of MTL105 compound that induce characteristic intrinsic apoptotic cell death, specifically in tumor cell lines at sub-µM concentrations with no effect on healthy cells, suggesting a strong safety margin. According to the NCI60 compare analysis, this compound constitutes a first-in-class product in cancer therapy with this MoA and would be particularly interesting to overcome multidrug-resistant cancers. Citation Format: Nelly Buron, Claire Pertuiset, Roxane Loyant, Cécile Martel, Mathieu Porceddu, Annie Borgne-Sanchez. Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 788.