LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models
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.
Authors
- Renato A. Bauer (ORCID: https://orcid.org/0000-0001-5352-6389)
- Anna Skwarska (ORCID: https://orcid.org/0000-0002-0979-026X)
- Courtney D. DiNardo (ORCID: https://orcid.org/0000-0001-9003-0390)
- Zoran Ranković (ORCID: https://orcid.org/0000-0001-6866-4290)
- Marina Konopleva (ORCID: https://orcid.org/0000-0002-9347-2212)
- John Strelow
- Kate Newell
- Jason R. Manro
- Mark H. Bender (ORCID: https://orcid.org/0009-0006-7918-4229)
- Jean‐Emmanuel Sarry (ORCID: https://orcid.org/0000-0002-6704-2032)
- Steven M. Chan (ORCID: https://orcid.org/0000-0002-4354-0731)
- Nathan A. Brooks (ORCID: https://orcid.org/0000-0002-5111-6914)
- Deepti Thete
- Vivian Salama (ORCID: https://orcid.org/0000-0002-4870-4635)
- Serge L. Boulet
- Raquel Torres
- Rebecca Leon
- Robert L. Johnson (ORCID: https://orcid.org/0000-0002-0478-6069)
- Raymond Gilmour (ORCID: https://orcid.org/0009-0003-4008-6267)
- Patric J. Hahn
- Timothy P. Burkholder
- Richard Romero
- Xueqian Gong (ORCID: https://orcid.org/0009-0005-5647-4090)
- Robin I. DeWalt (ORCID: https://orcid.org/0009-0000-2996-0054)
- Danalyn Manglicmot. Lagutan (ORCID: https://orcid.org/0009-0008-7351-0016)
- Rachel Cavitt (ORCID: https://orcid.org/0009-0007-3939-8019)
- Kenneth D. Roth (ORCID: https://orcid.org/0000-0002-3650-9808)
- Bryan Perria (ORCID: https://orcid.org/0009-0000-0546-526X)
- Lisa Kays (ORCID: https://orcid.org/0009-0007-9343-7314)
- Stephen Antonysamy (ORCID: https://orcid.org/0000-0003-1596-2790)
- Sandra Gomez (ORCID: https://orcid.org/0000-0003-1804-6405)
- Paul Milligan (ORCID: https://orcid.org/0009-0003-2083-0618)
Institutions
- West Virginia University (US)
- Albert Einstein College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- Institute of Cancer Research (GB)
- Inserm (FR)
- Eli Lilly (United States) (US)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Princess Margaret Cancer Centre (CA)
- Eli Lilly (United Kingdom) (GB)
- Eli Lilly (Spain) (ES)
- Arvinas (United States) (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1158/2643-3230.bcd-25-0379
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00