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New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

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.

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Figure 1: Identification of novel allosteric inhibitors of mutant IDH1.
Figure 2: Structural and biochemical characterization.
Figure 3: GSK321 decreases intracellular 2-HG and affects proliferation of primary IDH1 mutant AML cells.
Figure 4: Induction of differentiation in primary IDH1 mutant AML blasts and immature stem-like cells.
Figure 5: GSK321 leads to genome-wide DNA cytosine hypomethylation in IDH1 mutant AML cells.

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Acknowledgements

We thank D. Sun of the Einstein Human Stem Cell FACS and Xenotransplantation facility (supported by NYSTEM grant C024172) and J. Chen, C.K. Sheridan and F. Garrett-Bakelman of the Weill Cornell Medical College Epigenomics Core, and the Albert Einstein College of Medicine Epigenomics Core for expert technical assistance and advice. Funding: this work was supported by the Albert Einstein Cancer Center Core Support grant (P30CA013330), NYSTEM grant no. 24306 and GlaxoSmithKline (GSK). E.P. is supported by US National Institutes of Health (NIH) U24CA114737 and U10CA180827. U.C.O.-O. is supported by NIH F31CA162770 and the MSTP grant T32 GM007288. U.S. is a Research Scholar of the Leukemia & Lymphoma Society and is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine.

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U.C.O.-O., B.B., B.W., M.T.M., N.D.A., A.V., B.S. and U.S. designed the study and experiments; U.C.O.-O., E.N.G., B.P., A.R.R., C.R., C.Q., A.S., K.J.W., A.J.R., S.J.S., H.Q., H.Z., G.J., M.F.-S., M.B., G.D., C.D., P.B., A.G., J.C., I.A.-D., K.M., L.C., M.T.M., N.D.A., P.B., B.S., H.R.W., H.M., Y.-R.K. and L.B. performed research and analyzed data; B.B. performed bioinformatic analysis; U.C.O.-O., I.A.-D., K.M. and S.-R.N. conducted in vivo studies; U.C.O.-O., B.B., B.W., M.C., E.P., H.M., N.C., N.D.A., B.S., M.T.M., J.M., A.V. and U.S. interpreted experiments and directed the study; and U.C.O.-O., N.D.A., B.S., M.T.M. and U.S. wrote the manuscript. All authors discussed results and contributed to the writing and editing of the manuscript.

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Correspondence to Ulrich Steidl.

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Competing interests

This work was supported by GlaxoSmithKline (GSK), of which E.N.G., B.P., A.R.R., C.R., C.Q., A.S., K.J.W., A.J.R., S.J.S., H.Q., H.Z., G.J., M.F.-S., M.B., G.D., C.D., P.B., A.G., N.C., N.D.A., B.S. and M.T.M. are employees.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–11, Supplementary Figures 1–7 and Supplementary Notes. (PDF 3010 kb)

Supplementary Data Set 1

Chemoproteomic approach showing selectivity of GSK321 for IDH1 [QUP, quantified unique peptides] (PDF 524 kb)

Supplementary Data Set 2

Differentially expressed genes by microarray analysis (PDF 249 kb)

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Okoye-Okafor, U., Bartholdy, B., Cartier, J. et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol 11, 878–886 (2015). https://doi.org/10.1038/nchembio.1930

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