Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nat Med. 2018 Jul;24(7):1036-1046. doi: 10.1038/s41591-018-0052-4. Epub 2018 Jun 11.
Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.
代谢重编程是肿瘤生物学的一个新兴标志，也是肿瘤药物发现中一个积极探索的机会。人们已经投入了大量的精力来研究糖酵解的治疗靶向，而药物靶向线粒体氧化磷酸化（OXPHOS）在很大程度上仍未得到探索，部分原因是对 OXPHOS 必不可少的肿瘤环境的理解还不完整。在这里，我们报告了 IACS-010759 的发现，这是一种线粒体电子传输链复合物 I 的临床级小分子抑制剂。IACS-010759 治疗依赖 OXPHOS 的脑癌和急性髓系白血病（AML）模型，可强力抑制增殖并诱导细胞凋亡，这可能是由于能量耗竭和天冬氨酸产量减少导致核苷酸生物合成受损的综合作用。在脑癌和 AML 模型中，IACS-010759 在可耐受剂量下进行治疗，可在体内强烈抑制肿瘤生长。IACS-010759 目前正在复发/难治性 AML 和实体瘤的 1 期临床试验中进行评估。
