Authors
Nathan A Brooks, Anna Skwarska, Vivian Salama, Mark H Bender, Lisa Kays, Robin I DeWalt, Bryan Perria, Deepti Thete, Jason R Manro, Rachel Cavitt, Rebecca Leon, Sandra Gomez, Raquel Torres, John M Strelow, Paul Milligan, Kate Newell, Kenneth D Roth, Jean-Emmanuel Sarry, Steven M Chan, Danalyn Manglicmot Lagutan, Richard Romero, Stephen Antonysamy, Robert L Johnson, Xueqian Gong, Renato A Bauer, Timothy P Burkholder, Patric J Hahn, Zoran Rankovic, Serge L Boulet, Courtney D DiNardo, Marina Konopleva, Raymond Gilmour
Published in
Blood cancer discovery. Jul 23, 2026. Epub Jul 23, 2026.
Abstract
Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.
PMID:
42490065
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 7
- Comments 0