Program: Oral and Poster Abstracts
Type: Oral
Session: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Acute Myeloid Leukemia: Exploiting New Therapeutic Targets and Novel Technologies
Here, we report the development of novel allosteric inhibitors of mutant IDH1 for differentiation therapy of acute myeloid leukemia. A high-throughput biochemical screen targeting an IDH1 heterodimer composed of R132H and WT IDH1 led to the identification of a tetrahydropyrazolopyridine series of inhibitors. Structural and biochemical analyses revealed that these novel compounds bind to an allosteric site that does not contact any of the mutant residues in the enzymes active site and inhibit enzymatic turnover. The enzyme complex locked in the catalytically inactive conformation inhibits the production of the oncometabolite 2-hydroxyglutarate (2-HG). In biochemical studies, we observed potent inhibition of several different clinically relevant R132 mutants in the presence or absence of the cofactor NADPH, accompanied by significant decrease in H3K9me2 levels.
Allosteric inhibitor treatment of primary AML patients’ cells with different clinically relevant R132 mutants of IDH1 ex vivo uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block, increased cell death and induction of differentiation both at the level of leukemic blasts and immature stem-like cells. Allosteric inhibition of IDH1 also led to a decrease in blasts in an in vivo xenotransplantation model. At the molecular level, enhanced reduced representation bisulfite sequencing showed that treatment with allosteric IDH1 inhibitors led to a significant reversal of the DNA cytosine hypermethylation pattern induced by mutant IDH1, accompanied by gene expression changes of key sets of genes and pathways, including "Cell Cycle", "G1/S transition", "Cellular growth and proliferation", and "Cell death and survival".
Taken together, our findings provide novel insight into the cellular and molecular effects of inhibition of mutant IDH1 in primary AML patients’ cells. Furthermore, our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting of different mutant forms of IDH1 in leukemia, and opens new avenues for future investigations with these and other allosteric inhibitors for targeting mutant IDH1 in leukemia and other cancers.
Disclosures: Gao: GlaxoSmithKline: Employment . Pietrak: GlaxoSmithKline: Employment . Rendina: GlaxoSmithKline: Employment . Rominger: GlaxoSmithKline: Employment . Quinn: GlaxoSmithKline: Employment . Smallwood: GlaxoSmithKline: Employment . Wiggall: GlaxoSmithKline: Employment . Reif: GlaxoSmithKline: Employment . Schmidt: GlaxoSmithKline: Employment . Qi: GlaxoSmithKline: Employment . Zhao: GlaxoSmithKline: Employment . Joberty: GlaxoSmithKline: Employment . Faelth-Savitski: GlaxoSmithKline: Employment . Bantscheff: GlaxoSmithKline: Employment . Drewes: GlaxoSmithKline: Employment . Duraiswami: GlaxoSmithKline: Employment . Brady: GlaxoSmithKline: Employment . Concha: GlaxoSmithKline: Employment . Adams: GlaxoSmithKline: Employment . Schwartz: GlaxoSmithKline: Employment . McCabe: GlaxoSmithKline: Employment .
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