| Literature DB >> 26436839 |
Ujunwa C Okoye-Okafor1, Boris Bartholdy1, Jessy Cartier1, Enoch N Gao2, Beth Pietrak2, Alan R Rendina2, Cynthia Rominger3, Chad Quinn2, Angela Smallwood2, Kenneth J Wiggall3, Alexander J Reif3, Stanley J Schmidt3, Hongwei Qi2, Huizhen Zhao2, Gerard Joberty4, Maria Faelth-Savitski2, Marcus Bantscheff4, Gerard Drewes4, Chaya Duraiswami2, Pat Brady2, Arthur Groy2, Swathi-Rao Narayanagari1, Iléana Antony-Debre1, Kelly Mitchell1, Heng Rui Wang1, Yun-Ruei Kao1, Maximilian Christopeit5, Luis Carvajal1, Laura Barreyro1, Elisabeth Paietta6, Hideki Makishima7, Britta Will1, Nestor Concha2, Nicholas D Adams3, Benjamin Schwartz2, Michael T McCabe3, Jaroslav Maciejewski7, Amit Verma6,8,9,10, Ulrich Steidl1,6,9,10.
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.Entities:
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Year: 2015 PMID： 26436839 PMCID： PMC5155016 DOI： 10.1038/nchembio.1930
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040