| Literature DB >> 29892070 |
Jennifer R Molina1,2, Yuting Sun1,2, Marina Protopopova1,2, Sonal Gera1,2, Madhavi Bandi1,2, Christopher Bristow1,2, Timothy McAfoos1, Pietro Morlacchi1,3, Jeffrey Ackroyd4, Ahmed-Noor A Agip5, Gheath Al-Atrash6, John Asara7, Jennifer Bardenhagen1, Caroline C Carrillo8, Christopher Carroll1, Edward Chang1,2, Stefan Ciurea6, Jason B Cross1, Barbara Czako1, Angela Deem1,2, Naval Daver9, John Frederick de Groot8, Jian-Wen Dong8, Ningping Feng1,2, Guang Gao1,2, Jason Gay1,2, Mary Geck Do1, Jennifer Greer1, Virginia Giuliani1,2, Jing Han1,2, Lina Han9, Verlene K Henry8, Judy Hirst5, Sha Huang1, Yongying Jiang1, Zhijun Kang1, Tin Khor1,2, Sergej Konoplev10, Yu-Hsi Lin4, Gang Liu1, Alessia Lodi11, Timothy Lofton1, Helen Ma9, Mikhila Mahendra1,2, Polina Matre9, Robert Mullinax1,2, Michael Peoples1,2, Alessia Petrocchi1, Jaime Rodriguez-Canale12, Riccardo Serreli5, Thomas Shi1,2, Melinda Smith1,2, Yoko Tabe9,13, Jay Theroff1, Stefano Tiziani11, Quanyun Xu1, Qi Zhang9, Florian Muller4, Ronald A DePinho14, Carlo Toniatti1,2, Giulio F Draetta1,2,15, Timothy P Heffernan1,2, Marina Konopleva9, Philip Jones1, M Emilia Di Francesco1, Joseph R Marszalek16,17.
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.Entities:
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Year: 2018 PMID： 29892070 DOI： 10.1038/s41591-018-0052-4
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440