Abstract
A medicinal chemistry approach identified IACS-010759 as a clinical-grade small-molecule OXPHOS inhibitor.
Major finding: A medicinal chemistry approach identified IACS-010759 as a clinical-grade small-molecule OXPHOS inhibitor.
Concept: IACS-010759 has antitumor activity in models of AML, brain cancer, and SWI/SNF-mutant tumors.
Impact: IACS-010759 warrants further clinical investigation for the treatment of a variety of tumor types.
A subset of tumors exhibit a strong dependence on mitochondrial oxidative phosphorylation (OXPHOS), suggesting the potential for therapeutic targeting of OXPHOS in cancer. However, adequate therapeutics are not currently available to target OXPHOS in cancer. Through an extensive medicinal chemistry campaign of lead optimization initially seeded with known modulators of HIF1α, Molina, Sun, and colleagues developed a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain: IACS-010759. IACS-010759 inhibited OXPHOS and suppressed the growth of acute myeloid leukemia (AML) and glycolysis-deficient brain cancer cells. In vivo, IACS-010759 was well tolerated, extended survival, and suppressed tumor growth in models of AML, neuroblastoma, and brain cancer. These findings suggest that OXPHOS may be therapeutically targeted in cancer, and IACS-010759 is being evaluated in ongoing clinical trials. In a related study, Lissanu Deribe and colleagues found that IACS-010759 may also have antitumor activity in tumors with mutations in the SWI/SNF chromatin remodeling complex. Development of a genetically engineered mouse model of lung adenocarcinoma with loss of the SWI/SNF subunit gene Smarca4 revealed increased expression of OXPHOS genes, providing a rationale for investigating IACS-010759 treatment in these tumors. SMARCA4 expression was required for optimal expression of genes involved in the stress response to energy deprivation. In vivo, Smarca4-deficient lung tumors were sensitive to IACS-010759 treatment as were SWI/SNF-mutant tumor xenografts. The development of IACS-010759 may allow for therapeutic targeting of OXPHOS, and these preclinical studies suggest that it may have antitumor activity in a variety of malignancies including AML, brain cancer, and SWI/SNF mutant tumors. Further clinical investigation of IACS-010759 is currently under way.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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