LY3410738, a Covalent Inhibitor of Mutant IDH1/2, Is Effective in Acute Myeloid Leukemia Preclinical Models.

UNLABELLED: 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 (IDH) 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 present 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 (PDX) 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.

SIGNIFICANCE: LY3410738 represents a promising advancement in the treatment of IDH1/2-mutated AML. Its irreversible binding and targeting of both IDH1/2 isoforms, coupled with sustained activity against mIDH1/2 with acquired second-site resistance mutations, distinguishes LY3410738 from clinically available IDH inhibitors and suggests therapeutic potential for patients with AML resistant to standard IDH-based treatment.