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Publications

Journal Article Ahead of print

PubMed: 42490065 DOI: 10.1158/2643-3230.BCD-25-0379

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

Blood Cancer Discov

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

Affiliations

  • Eli Lilly (United States) Indianapolis, IN United States.
  • Albert Einstein College of Medicine Bronx, New York United States.
  • West Virginia University Morgantown, WV United States.
  • Eli Lilly and Company Indianapolis, IN United States.
  • Arvinas (United States) New Haven, CT United States.
  • Eli Lilly (United States) United States.
  • Eli Lilly (Spain) Alcobendas, Madrid, Spain Spain.
  • Eli Lilly and Company Alcobendas Spain.
  • Eli Lilly and Company United States.
  • Inserm and Universite de Toulouse Toulouse France.
  • Princess Margaret Cancer Centre Toronto Canada.
  • Eli Lilly and Company San DIego, CA United States.
  • Eli Lilly (United States) San Diego, Ca United States.
  • Eli Lilly and Company Indianapolis, Indiana United States.
  • Institute of Cancer Research Sutton United Kingdom.
  • The University of Texas MD Anderson Cancer Center Houston, TX United States.

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.

MeSH

Glioma, Blood, Leukemia, Leukemia, Myeloid, Acute, Leukemia, Myeloid, Mutation