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An inhibitor of oxidative phosphorylation exploits cancer vulnerability. 2018
Jennifer R Molina, and
Yuting Sun, and
Marina Protopopova, and
Sonal Gera, and
Madhavi Bandi, and
Christopher Bristow, and
Timothy McAfoos, and
Pietro Morlacchi, and
Jeffrey Ackroyd, and
Ahmed-Noor A Agip, and
Gheath Al-Atrash, and
John Asara, and
Jennifer Bardenhagen, and
Caroline C Carrillo, and
Christopher Carroll, and
Edward Chang, and
Stefan Ciurea, and
Jason B Cross, and
Barbara Czako, and
Angela Deem, and
Naval Daver, and
John Frederick de Groot, and
Jian-Wen Dong, and
Ningping Feng, and
Guang Gao, and
Jason Gay, and
Mary Geck Do, and
Jennifer Greer, and
Virginia Giuliani, and
Jing Han, and
Lina Han, and
Verlene K Henry, and
Judy Hirst, and
Sha Huang, and
Yongying Jiang, and
Zhijun Kang, and
Tin Khor, and
Sergej Konoplev, and
Yu-Hsi Lin, and
Gang Liu, and
Alessia Lodi, and
Timothy Lofton, and
Helen Ma, and
Mikhila Mahendra, and
Polina Matre, and
Robert Mullinax, and
Michael Peoples, and
Alessia Petrocchi, and
Jaime Rodriguez-Canale, and
Riccardo Serreli, and
Thomas Shi, and
Melinda Smith, and
Yoko Tabe, and
Jay Theroff, and
Stefano Tiziani, and
Quanyun Xu, and
Qi Zhang, and
Florian Muller, and
Ronald A DePinho, and
Carlo Toniatti, and
Giulio F Draetta, and
Timothy P Heffernan, and
Marina Konopleva, and
Philip Jones, and
M Emilia Di Francesco, and
Joseph R Marszalek
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
Related Publications
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Madhavi Bandi, and
Christopher Bristow, and
Timothy McAfoos, and
Pietro Morlacchi, and
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Ahmed-Noor A Agip, and
Gheath Al-Atrash, and
John Asara, and
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Caroline C Carrillo, and
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Jaime Rodriguez-Canale, and
Riccardo Serreli, and
Thomas Shi, and
Melinda Smith, and
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Jay Theroff, and
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Quanyun Xu, and
Qi Zhang, and
Florian Muller, and
Ronald A DePinho, and
Carlo Toniatti, and
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Florian Muller, and
Ronald A DePinho, and
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Jennifer Bardenhagen, and
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Verlene K Henry, and
Judy Hirst, and
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Yongying Jiang, and
Zhijun Kang, and
Tin Khor, and
Sergej Konoplev, and
Yu-Hsi Lin, and
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Alessia Lodi, and
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