An inhibitor of oxidative phosphorylation exploits cancer vulnerability
Open accessAbstract
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.
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Recently described OXPHOS inhibitors display enhanced toxicity against cultured cancer cells compared with nontransformed cells or other cancer cells that can compensate for OXPHOS impairment, and they suppress growth of susceptible tumors in mice at doses well tolerated over the short term.
“Recently described OXPHOS inhibitors display enhanced toxicity against cultured cancer cells compared with either nontransformed cells or other cancer cells with metabolic properties that allow them to compensate for OXPHOS impairment (116, 117). It is encouraging that these agents also suppress growth of susceptible tumors in mice, using doses that are well-tolerated over the short term.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [116]
An OXPHOS inhibitor with potent efficacy in mouse models is now in phase 1 clinical trials.
“an OXPHOS inhibitor with potent efficacy in mouse models is now in phase 1 clinical trials (116).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [116]
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- Authors
- Molina, J. R., Sun, Y., Protopopova, M., Gera, S., Bandi, M., Bristow, C., McAfoos, T., Morlacchi, P., Ackroyd, J., Agip, A.-N. A., Al-Atrash, G., Asara, J., Bardenhagen, J., Carrillo, C. C., Carroll, C., Chang, E., Ciurea, S., Cross, J. B., Czako, B., Deem, A., Daver, N., de Groot, J. F., Dong, J.-W., Feng, N., Gao, G., Gay, J., Do, M. G., Greer, J., Giuliani, V., Han, J., Han, L., Henry, V. K., Hirst, J., Huang, S., Jiang, Y., Kang, Z., Khor, T., Konoplev, S., Lin, Y.-H., Liu, G., Lodi, A., Lofton, T., Ma, H., Mahendra, M., Matre, P., Mullinax, R., Peoples, M., Petrocchi, A., Rodriguez-Canale, J., Serreli, R., Shi, T., Smith, M., Tabe, Y., Theroff, J., Tiziani, S., Xu, Q., Zhang, Q., Muller, F., DePinho, R. A., Toniatti, C., Draetta, G. F., Heffernan, T. P., Konopleva, M., Jones, P., Di Francesco, M. E., & Marszalek, J. R.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Cambridge (GB)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas at Austin (US)
- Corresponding author
- Marszalek, Joseph R.
- ORCID
- Sun, Yuting
- Protopopova, Marina
- Gera, Sonal
- Bandi, Madhavi
- Bristow, Christopher
- Ackroyd, Jeffrey
- Agip, Ahmed-Noor A.
- Asara, John
- Bardenhagen, Jennifer
- Ciurea, Stefan
- Cross, Jason B.
- Deem, Angela
- Daver, Naval
- Feng, Ningping
- Giuliani, Virginia
- Han, Jing
- Han, Lina
- Hirst, Judy
- Huang, Sha
- Jiang, Yongying
- Konoplev, Sergej
- Lin, Yu-Hsi
- Liu, Gang
- Lodi, Alessia
- Ma, Helen
- Mahendra, Mikhila
- Matre, Polina
- Peoples, Michael
- Tabe, Yoko
- Tiziani, Stefano
- Zhang, Qi
- Muller, Florian
- DePinho, Ronald A.
- Toniatti, Carlo
- Draetta, Giulio F.
- Heffernan, Timothy P.
- Konopleva, Marina
- Jones, Philip
- Marszalek, Joseph R.
- Venue
- Nature Medicine
- Published
- 2018-06-11
- Volume
- 24
- Issue
- 7
- Pages
- 1036-1046
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2806128074
- Cited by
- 928
- References
- 55
- Citations by year
- 2026: 93 · 2025: 113 · 2024: 125 · 2023: 143 · 2022: 121 · 2021: 144 · 2020: 110 · 2019: 67 · 2018: 12
- FWCI
- 25.10
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Medical Research Council (MC_UU_00015/7)
- Japan Society for the Promotion of Science (15K08653)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- IACS-010759, oxidative phosphorylation inhibition, complex I inhibitors, mitochondrial electron transport chain, tumor metabolic reprogramming, acute myeloid leukemia, brain cancer, nucleotide synthesis, energy depletion, apoptosis, tumor growth inhibition
- MeSH terms
- Animals, Energy Metabolism, Glycolysis, Humans, Mitochondria, Neoplasms, Nucleotides, Oxidative Phosphorylation, Biomarkers, Tumor, Leukemia, Myeloid, Acute, Lactic Acid, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Mice, HEK293 Cells
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