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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Molina JR,Sun Y,Protopopova M,Gera S,Bandi M,Bristow C,McAfoos T,Morlacchi P,Ackroyd J,Agip AA,Al-Atrash G,Asara J,Bardenhagen J,Carrillo CC,Carroll C,Chang E,Ciurea S,Cross JB,Czako B,Deem A,Daver N,de Groot JFdoi
10.1038/s41591-018-0052-4subject
Has Abstractpub_date
2018-07-01 00:00:00pages
1036-1046issue
7eissn
1078-8956issn
1546-170Xpii
10.1038/s41591-018-0052-4journal_volume
24pub_type
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