New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

Nat Chem Biol. 2015 Nov;11(11):878-86. doi: 10.1038/nchembio.1930. Epub 2015 Oct 5.

Abstract

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • CpG Islands
  • Crystallography, X-Ray
  • Cytosine / chemistry
  • Cytosine / metabolism
  • DNA Methylation / drug effects
  • Dihydropyridines / chemistry
  • Dihydropyridines / pharmacokinetics
  • Dihydropyridines / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Granulocytes / drug effects
  • Granulocytes / enzymology
  • Granulocytes / pathology
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / chemistry
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Kinetics
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Models, Molecular
  • Mutation
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / pathology
  • Primary Cell Culture
  • Protein Binding
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Dihydropyridines
  • Enzyme Inhibitors
  • Pyrazoles
  • Cytosine
  • Isocitrate Dehydrogenase
  • IDH1 protein, human

Associated data

  • GEO/GSE72152
  • GEO/GSE72253
  • PDB/5DE1
  • PubChem-Substance/252300989
  • PubChem-Substance/252300990
  • PubChem-Substance/252300991
  • PubChem-Substance/252300992
  • PubChem-Substance/252300993
  • PubChem-Substance/252300994
  • PubChem-Substance/252300995
  • PubChem-Substance/252300996
  • PubChem-Substance/252300997
  • PubChem-Substance/252300998
  • PubChem-Substance/252300999
  • PubChem-Substance/252301000
  • PubChem-Substance/252301001
  • PubChem-Substance/252301002
  • PubChem-Substance/252301003
  • PubChem-Substance/252301004
  • PubChem-Substance/252301005
  • PubChem-Substance/252301006
  • PubChem-Substance/252301007
  • PubChem-Substance/252301008
  • PubChem-Substance/252301009
  • PubChem-Substance/252301010
  • PubChem-Substance/252301011
  • PubChem-Substance/252301012
  • PubChem-Substance/252301013
  • PubChem-Substance/252301014
  • PubChem-Substance/252301015