New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
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新的IDH1突变抑制剂治疗急性髓样白血病。
DOI：
10.1038/nchembio.1930
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发表时间：
2015-11
影响因子：
14.8
通讯作者：
Steidl, Ulrich
中科院分区：
文献类型：
--
作者：
Okoye-Okafor, Ujunwa C.;Bartholdy, Boris;Cartier, Jessy;Gao, Enoch N.;Pietrak, Beth;Rendina, Alan R.;Rominger, Cynthia;Quinn, Chad;Smallwood, Angela;Wiggall, Kenneth J.;Reif, Alexander J.;Schmidt, Stanley J.;Qi, Hongwei;Zhao, Huizhen;Joberty, Gerard;Faelth-Savitski, Maria;Bantscheff, Marcus;Drewes, Gerard;Duraiswami, Chaya;Brady, Pat;Groy, Arthur;Narayanagari, Swathi-Rao;Antony-Debre, Ileana;Mitchell, Kelly;Wang, Heng Rui;Kao, Yun-Ruei;Christopeit, Maximilian;Carvajal, Luis;Barreyro, Laura;Paietta, Elisabeth;Makishima, Hideki;Will, Britta;Concha, Nestor;Adams, Nicholas D.;Schwartz, Benjamin;McCabe, Michael T.;Maciejewski, Jaroslav;Verma, Amit;Steidl, Ulrich
异柠檬酸脱氢酶1（IDH 1）中的新变体突变是急性髓性白血病（AML）和其他癌症中的驱动突变。我们报告了突变IDH 1的新变构抑制剂的开发。晶体学和生物化学结果表明，该化学系列的化合物与变构位点结合，并将酶锁定在催化失活构象，从而能够抑制不同的临床相关IDH 1突变体。在体外和体内，IDH 1突变原代AML细胞的治疗均匀地导致细胞内2-HG的减少，髓样分化阻滞的消除和在白血病母细胞和更不成熟的干细胞样细胞水平的粒细胞分化的诱导。在分子上，用抑制剂治疗导致AML患者细胞中由突变IDH 1引起的DNA胞嘧啶超甲基化模式逆转。我们的研究为新型变构抑制剂靶向白血病中IDH 1不同突变形式的分子和生物学活性提供了概念验证。
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 AML patients’ cells. 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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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
10.5
作者：
Lu C;Venneti S;Akalin A;Fang F;Ward PS;Dematteo RG;Intlekofer AM;Chen C;Ye J;Hameed M;Nafa K;Agaram NP;Cross JR;Khanin R;Mason CE;Healey JH;Lowe SW;Schwartz GK;Melnick A;Thompson CB
通讯作者：
Thompson CB
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
11.4
作者：
Kruse, U.;Pallasch, C. P.;Drewes, G.
通讯作者：
Drewes, G.