An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Abstract

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.

Activation of LXR β inhibits tumor respiration and is synthetically lethal with Bcl‐ xL inhibition

“…Our result suggests that glutamine deprivation sensitizes for LXR activation‐driven cell death (Appendix Fig ). Considering the levels of essential and non‐essential amino acids, we found that especially aspartate levels were suppressed, which is in keeping with earlier reports, demonstrating that under conditions of inhibition with OXPHOS, aspartate becomes critical for tumors to survive and grow (Appendix Fig ; Molina et al , ). Overall, these findings are consistent with a profound reprogramming of the TCA cycle reactions by LXR agonists.…”

“…In agreement, the TCA cycle metabolites were altered and carbon tracing experiments showed decreased labeling by glucose‐derived carbons. We noted a decrease in labeling of the amino acid aspartate and nucleotides by glucose carbons, which is line with prior studies, that inhibition of OXPHOS depletes both aspartate and nucleotides, which in turn can elicit the induction of a potential DNA‐stress response (Molina et al , ). Through our glutamine tracing experiment, we have found that LXR activation renders tumor cells partially more dependent on glutamine for their survival.…”

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

“…Several compounds block complex I (official name: NADH:ubiquinone oxidoreductase) with high affinity: BAY87‐2243, IACS‐010759, and ME‐344 . The growth‐inhibitory effects of BAY87‐2243 and IACS‐010759 are abolished in human cancer cells manipulated to express a yeast enzyme that bypasses complex I (the NDI1 NADH‐ Q ‐oxidoreductase that does not translocate protons and, in yeast mitochondria, substitutes the role of complex I), supporting the idea that they specifically act on target . Some of these inhibitors have been introduced into phase I trials, yielding signs of toxicity for BAY87‐2243 (which caused grade III nausea/vomiting, http://ClinicalTrials.gov NCT01297530) (Table ) and no signal of clinical efficacy for ME‐344 .…”

“…Several compounds block complex I (official name: NADH: ubiquinone oxidoreductase) with high affinity: BAY87-2243, 42 IACS-010759, 14,43 and ME-344. 22 The growth-inhibitory effects of BAY87-2243 and IACS-010759 are abolished in human cancer cells manipulated to express a yeast enzyme that bypasses complex I (the NDI1 NADH-Q-oxidoreductase that does not translocate protons and, in yeast mitochondria, substitutes the role of complex I), supporting the idea that they specifically act on target.…”

“…22 The growth-inhibitory effects of BAY87-2243 and IACS-010759 are abolished in human cancer cells manipulated to express a yeast enzyme that bypasses complex I (the NDI1 NADH-Q-oxidoreductase that does not translocate protons and, in yeast mitochondria, substitutes the role of complex I), supporting the idea that they specifically act on target. 42,43 Some of these inhibitors have been introduced into phase I trials, yielding signs of toxicity for BAY87-2243 (which caused grade III nausea/vomiting, ClinicalTrials.gov NCT01297530) ( Table 1) and no signal of clinical efficacy for ME-344. 44 Hence, further clinical optimization (perhaps in combination with other agents) will be required for the development of such agents.…”