An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Jennifer R. Molina, Yuting Sun, Marina Protopopova, Sonal Gera, Madhavi Bandi, Christopher Bristow, Timothy McAfoos, Pietro Morlacchi, Jeffrey Ackroyd, Ahmed Noor A. Agip, Gheath Al-Atrash, John Asara, Jennifer Bardenhagen, Caroline C. Carrillo, Christopher Carroll, Edward Chang, Stefan Ciurea, Jason B. Cross, Barbara Czako, Angela DeemNaval Daver, John Frederick De Groot, Jian Wen Dong, Ningping Feng, Guang Gao, Jason Gay, Mary Geck Do, Jennifer Greer, Virginia Giuliani, Jing Han, Lina Han, Verlene K. Henry, Judy Hirst, Sha Huang, Yongying Jiang, Zhijun Kang, Tin Khor, Sergej Konoplev, Yu Hsi Lin, Gang Liu, Alessia Lodi, Timothy Lofton, Helen Ma, Mikhila Mahendra, Polina Matre, Robert Mullinax, Michael Peoples, Alessia Petrocchi, Jaime Rodriguez-Canale, Riccardo Serreli, Thomas Shi, Melinda Smith, Yoko Tabe, Jay Theroff, Stefano Tiziani, Quanyun Xu, Qi Zhang, Florian Muller, Ronald A. Depinho, Carlo Toniatti, Giulio F. Draetta, Timothy P. Heffernan, Marina Konopleva, Philip Jones, M. Emilia Di Francesco, Joseph R. Marszalek

Research output: Contribution to journalArticlepeer-review

264 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1036-1046
Number of pages11
JournalNature medicine
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • High Resolution Electron Microscopy Facility
  • Research Animal Support Facility
  • Small Animal Imaging Facility
  • Cytogenetics and Cell Authentication Core

Fingerprint

Dive into the research topics of 'An inhibitor of oxidative phosphorylation exploits cancer vulnerability'. Together they form a unique fingerprint.

Cite this