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Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Isocitrate Dehydrogenase 2 Inhibitors for the Treatment of Hematologic Malignancies: Advances and Future Opportunities

Author(s): Feng Huang, Tian Tian, Yizhe Wu, Jinxin Che, Haiyan Yang* and Xiaowu Dong*

Volume 21, Issue 9, 2021

Published on: 30 November, 2020

Page: [1113 - 1122] Pages: 10

DOI: 10.2174/1389557520666201130102724

Price: $65


Tumor cells frequently reprogram cellular metabolism from oxidative phosphorylation to glycolysis. Isocitrate dehydrogenase 2 (IDH2) has been intensively studied due to its involvement in the metabolic activity of cancer cells. Mutations in IDH2 promote neomorphic activity through the generation of oncometabolite 2-hydroxyglutarate (2-HG). The overproduced 2-HG can competitively inhibit α-KG-dependent dioxygenases to trigger cell differentiation disorders, a major cause of blood tumors. This review outlines recent progress in the identification of IDH2 inhibitors in blood cancer to provide a reference for ongoing and future clinical studies.

Keywords: Isocitrate dehydrogenase 2, IDH2, mutant, inhibitors, structure-activity relationship, blood cancer.

Graphical Abstract
Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 2009, 324(5930), 1029-1033.
[] [PMID: 19460998]
DeBerardinis, R.J.; Lum, J.J.; Hatzivassiliou, G.; Thompson, C.B. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab., 2008, 7(1), 11-20.
[] [PMID: 18177721]
Nagarajan, A.; Malvi, P.; Wajapeyee, N. Oncogene-directed alterations in cancer cell metabolism. Trends Cancer, 2016, 2(7), 365-377.
[] [PMID: 27822561]
Dang, C.V. Links between metabolism and cancer. Genes Dev., 2012, 26(9), 877-890.
[] [PMID: 22549953]
Sradhanjali, S.; Reddy, M.M. Inhibition of pyruvate dehydrogenase kinase as a therapeutic strategy against cancer. Curr. Top. Med. Chem., 2018, 18(6), 444-453.
[] [PMID: 29788890]
Galluzzi, L.; Kepp, O.; Vander Heiden, M.G.; Kroemer, G. Metabolic targets for cancer therapy. Nat. Rev. Drug Discov., 2013, 12(11), 829-846.
[] [PMID: 24113830]
Matés, J.M.; Di Paola, F.J.; Campos-Sandoval, J.A.; Mazurek, S.; Márquez, J. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin. Cell Dev. Biol., 2020, 98, 34-43.
[] [PMID: 31100352]
Parsons, D.W.; Jones, S.; Zhang, X.; Lin, J.C-H.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Siu, I.M.; Gallia, G.L.; Olivi, A.; McLendon, R.; Rasheed, B.A.; Keir, S.; Nikolskaya, T.; Nikolsky, Y.; Busam, D.A.; Tekleab, H.; Diaz, L.A., Jr; Hartigan, J.; Smith, D.R.; Strausberg, R.L.; Marie, S.K.N.; Shinjo, S.M.O.; Yan, H.; Riggins, G.J.; Bigner, D.D.; Karchin, R.; Papadopoulos, N.; Parmigiani, G.; Vogelstein, B.; Velculescu, V.E.; Kinzler, K.W. An integrated genomic analysis of human glioblastoma multiforme. Science, 2008, 321(5897), 1807-1812.
[] [PMID: 18772396]
Ward, P.S.; Patel, J.; Wise, D.R.; Abdel-Wahab, O.; Bennett, B.D.; Coller, H.A.; Cross, J.R.; Fantin, V.R.; Hedvat, C.V.; Perl, A.E.; Rabinowitz, J.D.; Carroll, M.; Su, S.M.; Sharp, K.A.; Levine, R.L.; Thompson, C.B. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell, 2010, 17(3), 225-234.
[] [PMID: 20171147]
Molenaar, R.J.; Radivoyevitch, T.; Maciejewski, J.P.; van Noorden, C.J.F.; Bleeker, F.E. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation.Biochim. Biophys. Acta,, 2014, 1846(2), 326-341.
[PMID: 24880135]
Cairns, R.A.; Mak, T.W. Oncogenic isocitrate dehydrogenase mutations: Mechanisms, models, and clinical opportunities. Cancer Discov., 2013, 3(7), 730-741.
[] [PMID: 23796461]
Gross, S.; Cairns, R.A.; Minden, M.D.; Driggers, E.M.; Bittinger, M.A.; Jang, H.G.; Sasaki, M.; Jin, S.; Schenkein, D.P.; Su, S.M.; Dang, L.; Fantin, V.R.; Mak, T.W. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med., 2010, 207(2), 339-344.
[] [PMID: 20142433]
Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; Marks, K.M.; Prins, R.M.; Ward, P.S.; Yen, K.E.; Liau, L.M.; Rabinowitz, J.D.; Cantley, L.C.; Thompson, C.B.; Vander Heiden, M.G.; Su, S.M. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 2009, 462(7274), 739-744.
[] [PMID: 19935646]
Goh, T.S.; Hong, C. New insights of common gamma chain in hematological malignancies. Cytokine, 2017, 89, 179-184.
[] [PMID: 26748725]
Xu, W.; Yang, H.; Liu, Y.; Yang, Y.; Wang, P.; Kim, S.H.; Ito, S.; Yang, C.; Wang, P.; Xiao, M.T.; Liu, L.X.; Jiang, W.Q.; Liu, J.; Zhang, J.Y.; Wang, B.; Frye, S.; Zhang, Y.; Xu, Y.H.; Lei, Q.Y.; Guan, K.L.; Zhao, S.M.; Xiong, Y. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell, 2011, 19(1), 17-30.
[] [PMID: 21251613]
Figueroa, M.E.; Abdel-Wahab, O.; Lu, C.; Ward, P.S.; Patel, J.; Shih, A.; Li, Y.; Bhagwat, N.; Vasanthakumar, A.; Fernandez, H.F.; Tallman, M.S.; Sun, Z.; Wolniak, K.; Peeters, J.K.; Liu, W.; Choe, S.E.; Fantin, V.R.; Paietta, E.; Löwenberg, B.; Licht, J.D.; Godley, L.A.; Delwel, R.; Valk, P.J.M.; Thompson, C.B.; Levine, R.L.; Melnick, A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell, 2010, 18(6), 553-567.
[] [PMID: 21130701]
Wouters, B.J. Hitting the target in IDH2 mutant AML. Blood, 2017, 130(6), 693-694.
[] [PMID: 28798056]
Ito, S.; D’Alessio, A.C.; Taranova, O.V.; Hong, K.; Sowers, L.C.; Zhang, Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature, 2010, 466(7310), 1129-1133.
[] [PMID: 20639862]
Dawlaty, M.M.; Breiling, A.; Le, T.; Barrasa, M.I.; Raddatz, G.; Gao, Q.; Powell, B.E.; Cheng, A.W.; Faull, K.F.; Lyko, F.; Jaenisch, R. Loss of Tet enzymes compromises proper differentiation of embryonic stem cells. Dev. Cell, 2014, 29(1), 102-111.
[] [PMID: 24735881]
Koivunen, P.; Lee, S.; Duncan, C.G.; Lopez, G.; Lu, G.; Ramkissoon, S.; Losman, J.A.; Joensuu, P.; Bergmann, U.; Gross, S.; Travins, J.; Weiss, S.; Looper, R.; Ligon, K.L.; Verhaak, R.G.W.; Yan, H.; Kaelin, W.G., Jr Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature, 2012, 483(7390), 484-488.
[] [PMID: 22343896]
Sasaki, M.; Knobbe, C.B.; Itsumi, M.; Elia, A.J.; Harris, I.S.; Chio, I.I.C.; Cairns, R.A.; McCracken, S.; Wakeham, A.; Haight, J.; Ten, A.Y.; Snow, B.; Ueda, T.; Inoue, S.; Yamamoto, K.; Ko, M.; Rao, A.; Yen, K.E.; Su, S.M.; Mak, T.W. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev., 2012, 26(18), 2038-2049.
[] [PMID: 22925884]
Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; von Kriegsheim, A.; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 2001, 292(5516), 468-472.
[] [PMID: 11292861]
Heuser, M.; Araujo Cruz, M.M.; Goparaju, R.; Chaturvedi, A. Enigmas of IDH mutations in hematology/oncology. Exp. Hematol., 2015, 43(8), 685-697.
[] [PMID: 26032956]
Khatami, F.; Aghamir, S. M. K.; Tavangar, S. M. Oncometabolites: A new insight for oncology.Mol. Genet. Genom. Med.,, 2019, 7(9)
Parker, S.J.; Metallo, C.M. Metabolic consequences of oncogenic IDH mutations. Pharmacol. Ther., 2015, 152, 54-62.
[] [PMID: 25956465]
Sharma, H. Development of novel therapeutics targeting isocitrate dehydrogenase mutations in cancer. Curr. Top. Med. Chem., 2018, 18(6), 505-524.
[] [PMID: 29773061]
Mardis, E.R.; Ding, L.; Dooling, D.J.; Larson, D.E.; McLellan, M.D.; Chen, K.; Koboldt, D.C.; Fulton, R.S.; Delehaunty, K.D.; McGrath, S.D.; Fulton, L.A.; Locke, D.P.; Magrini, V.J.; Abbott, R.M.; Vickery, T.L.; Reed, J.S.; Robinson, J.S.; Wylie, T.; Smith, S.M.; Carmichael, L.; Eldred, J.M.; Harris, C.C.; Walker, J.; Peck, J.B.; Du, F.; Dukes, A.F.; Sanderson, G.E.; Brummett, A.M.; Clark, E.; McMichael, J.F.; Meyer, R.J.; Schindler, J.K.; Pohl, C.S.; Wallis, J.W.; Shi, X.; Lin, L.; Schmidt, H.; Tang, Y.; Haipek, C.; Wiechert, M.E.; Ivy, J.V.; Kalicki, J.; Elliott, G.; Ries, R.E.; Payton, J.E.; Westervelt, P.; Tomasson, M.H.; Watson, M.A.; Baty, J.; Heath, S.; Shannon, W.D.; Nagarajan, R.; Link, D.C.; Walter, M.J.; Graubert, T.A.; DiPersio, J.F.; Wilson, R.K.; Ley, T.J. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med., 2009, 361(11), 1058-1066.
[] [PMID: 19657110]
Kosmider, O.; Gelsi-Boyer, V.; Slama, L.; Dreyfus, F.; Beyne-Rauzy, O.; Quesnel, B.; Hunault-Berger, M.; Slama, B.; Vey, N.; Lacombe, C.; Solary, E.; Birnbaum, D.; Bernard, O.A.; Fontenay, M. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia, 2010, 24(5), 1094-1096.
[] [PMID: 20376084]
Im, A.P.; Sehgal, A.R.; Carroll, M.P.; Smith, B.D.; Tefferi, A.; Johnson, D.E.; Boyiadzis, M. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: Associations with prognosis and potential treatment strategies. Leukemia, 2014, 28(9), 1774-1783.
[] [PMID: 24699305]
Cairns, R.A.; Iqbal, J.; Lemonnier, F.; Kucuk, C.; de Leval, L.; Jais, J.P.; Parrens, M.; Martin, A.; Xerri, L.; Brousset, P.; Chan, L.C.; Chan, W.C.; Gaulard, P.; Mak, T.W. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood, 2012, 119(8), 1901-1903.
[] [PMID: 22215888]
Broutin, S.; Lemonnier, F.; Dupuy, A.; Delahousse, J.; Fataccioli, V.; Ribrag, V.; Safar, V.; Pelletier, L.; Robe, C.; Tilly, H.; Cottereau, A.S.; Bossard, C.; de Leval, L.; Delfau, M-H.; Haioun, C.; Paci, A.; Gaulard, P. Serum 2-hydroxyglutarate in angioimmunoblastic T cell lymphomas: A new marker for IDH2 mutation detection and monitoring. Blood, 2018, 132(Suppl. 1), 2898-2898.
Dupuy, A.; Lemonnier, F.; Fataccioli, V.; Martin-Garcia, N.; Robe, C.; Pelletier, R.; Poullot, E.; Moktefi, A.; Mokhtari, K.; Rousselet, M.C.; Traverse-Glehen, A.; Delarue, R.; Tournilhac, O.; Delfau-Larue, M.H.; Haioun, C.; Ortonne, N.; Copie-Bergman, C.; de Leval, L.; Pujals, A.; Gaulard, P. Multiple ways to detect IDH2 mutations in angioimmunoblastic T-cell lymphoma from immunohistochemistry to next-generation sequencing. J. Mol. Diagn., 2018, 20(5), 677-685.
[] [PMID: 29981867]
Lemonnier, F.; Cairns, R.A.; Inoue, S.; Li, W.Y.; Dupuy, A.; Broutin, S.; Martin, N.; Fataccioli, V.; Pelletier, R.; Wakeham, A.; Snow, B.E.; de Leval, L.; Pujals, A.; Haioun, C.; Paci, A.; Tobin, E.R.; Narayanaswamy, R.; Yen, K.; Jin, S.; Gaulard, P.; Mak, T.W. The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development. Proc. Natl. Acad. Sci. USA, 2016, 113(52), 15084-15089.
[] [PMID: 27956631]
Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute myeloid leukemia. N. Engl. J. Med., 2015, 373(12), 1136-1152.
[] [PMID: 26376137]
Bose, P.; Vachhani, P.; Cortes, J.E. Treatment of relapsed/refractory acute myeloid leukemia. Curr. Treat. Options Oncol., 2017, 18(3), 17.
[] [PMID: 28286924]
Washington, U. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med., 2009, 361(11), 1058-1066.
Metzeler, K.H.; Herold, T.; Rothenberg-Thurley, M.; Amler, S.; Sauerland, M.C.; Görlich, D.; Schneider, S.; Konstandin, N.P.; Dufour, A.; Bräundl, K.; Ksienzyk, B.; Zellmeier, E.; Hartmann, L.; Greif, P.A.; Fiegl, M.; Subklewe, M.; Bohlander, S.K.; Krug, U.; Faldum, A.; Berdel, W.E.; Wörmann, B.; Büchner, T.; Hiddemann, W.; Braess, J.; Spiekermann, K.; Grp, A.S. AMLCG study group. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood, 2016, 128(5), 686-698.
[] [PMID: 27288520]
DiNardo, C.D.; Ravandi, F.; Agresta, S.; Konopleva, M.; Takahashi, K.; Kadia, T.; Routbort, M.; Patel, K.P. Mark Brandt; Pierce, S.; Garcia-Manero, G.; Cortes, J.; Kantarjian, H. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am. J. Hematol., 2015, 90(8), 732-736.
[] [PMID: 26016821]
Silva, P.; Neumann, M.; Schroeder, M.P.; Vosberg, S.; Schlee, C.; Isaakidis, K.; Ortiz-Tanchez, J.; Fransecky, L.R.; Hartung, T.; Türkmen, S.; Graf, A.; Krebs, S.; Blum, H.; Müller-Tidow, C.; Thiede, C.; Ehninger, G.; Serve, H.; Hecht, J.; Berdel, W.E.; Greif, P.A.; Röllig, C.; Baldus, C.D. Acute myeloid leukemia in the elderly is characterized by a distinct genetic and epigenetic landscape. Leukemia, 2017, 31(7), 1640-1644.
[] [PMID: 28366934]
Papaemmanuil, E.; Gerstung, M.; Bullinger, L.; Gaidzik, V.I.; Paschka, P.; Roberts, N.D.; Potter, N.E.; Heuser, M.; Thol, F.; Bolli, N.; Gundem, G.; Van Loo, P.; Martincorena, I.; Ganly, P.; Mudie, L.; McLaren, S.; O’Meara, S.; Raine, K.; Jones, D.R.; Teague, J.W.; Butler, A.P.; Greaves, M.F.; Ganser, A.; Döhner, K.; Schlenk, R.F.; Döhner, H.; Campbell, P.J. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med., 2016, 374(23), 2209-2221.
[] [PMID: 27276561]
Chotirat, S.; Thongnoppakhun, W.; Promsuwicha, O.; Boonthimat, C.; Auewarakul, C.U. Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. J. Hematol. Oncol., 2012, 5, 5.
[] [PMID: 22397365]
Abbas, S.; Lugthart, S.; Kavelaars, F.G.; Schelen, A.; Koenders, J.E.; Zeilemaker, A.; van Putten, W.J.; Rijneveld, A.W.; Löwenberg, B.; Valk, P.J. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: Prevalence and prognostic value. Blood, 2010, 116(12), 2122-2126.
[] [PMID: 20538800]
Marcucci, G.; Maharry, K.; Wu, Y.Z.; Radmacher, M.D.; Mrózek, K.; Margeson, D.; Holland, K.B.; Whitman, S.P.; Becker, H.; Schwind, S.; Metzeler, K.H.; Powell, B.L.; Carter, T.H.; Kolitz, J.E.; Wetzler, M.; Carroll, A.J.; Baer, M.R.; Caligiuri, M.A.; Larson, R.A.; Bloomfield, C.D. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study. J. Clin. Oncol., 2010, 28(14), 2348-2355.
[] [PMID: 20368543]
Paschka, P.; Schlenk, R.F.; Gaidzik, V.I.; Habdank, M.; Krönke, J.; Bullinger, L.; Späth, D.; Kayser, S.; Zucknick, M.; Götze, K.; Horst, H.A.; Germing, U.; Döhner, H.; Döhner, K. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol., 2010, 28(22), 3636-3643.
[] [PMID: 20567020]
Feng, J.H.; Guo, X.P.; Chen, Y.Y.; Wang, Z.J.; Cheng, Y.P.; Tang, Y.M. Prognostic significance of IDH1 mutations in acute myeloid leukemia: A meta-analysis.Am. J. Blood Res.,, 2012, 2(4), 254-264.
[PMID: 23226625]
Boissel, N.; Nibourel, O.; Renneville, A.; Huchette, P.; Dombret, H.; Preudhomme, C. Differential prognosis impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood, 2011, 117(13), 3696-3697.
[] [PMID: 21454467]
Green, C.L.; Evans, C.M.; Zhao, L.; Hills, R.K.; Burnett, A.K.; Linch, D.C.; Gale, R.E. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood, 2011, 118(2), 409-412.
[] [PMID: 21596855]
Lin, C.C.; Hou, H.A.; Chou, W.C.; Kuo, Y.Y.; Liu, C.Y.; Chen, C.Y.; Lai, Y.J.; Tseng, M.H.; Huang, C.F.; Chiang, Y.C.; Lee, F.Y.; Liu, M.C.; Liu, C.W.; Tang, J.L.; Yao, M.; Huang, S.Y.; Ko, B.S.; Wu, S.J.; Tsay, W.; Chen, Y.C.; Tien, H.F. IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am. J. Hematol., 2014, 89(2), 137-144.
[] [PMID: 24115220]
Patnaik, M.M.; Hanson, C.A.; Hodnefield, J.M.; Lasho, T.L.; Finke, C.M.; Knudson, R.A.; Ketterling, R.P.; Pardanani, A.; Tefferi, A. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: A Mayo clinic study of 277 patients. Leukemia, 2012, 26(1), 101-105.
[] [PMID: 22033490]
Thol, F.; Weissinger, E.M.; Krauter, J.; Wagner, K.; Damm, F.; Wichmann, M.; Göhring, G.; Schumann, C.; Bug, G.; Ottmann, O.; Hofmann, W.K.; Schlegelberger, B.; Ganser, A.; Heuser, M. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica, 2010, 95(10), 1668-1674.
[] [PMID: 20494930]
Jin, J.; Hu, C.; Yu, M.; Chen, F.; Ye, L.; Yin, X.; Zhuang, Z.; Tong, H. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: A retrospective cohort study and meta-analysis. PLoS One, 2014, 9(6)e100206
[] [PMID: 24936872]
Medeiros, B.C.; Fathi, A.T.; DiNardo, C.D.; Pollyea, D.A.; Chan, S.M.; Swords, R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia, 2017, 31(2), 272-281.
[] [PMID: 27721426]
Lin, P.; Luo, Y.; Zhu, S.; Maggio, D.; Yang, H.; Hu, C.; Wang, J.; Zhang, H.; Ren, Y.; Zhou, X.; Mei, C.; Ma, L.; Xu, W.; Ye, L.; Zhuang, Z.; Jin, J.; Tong, H. Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes. J. Cancer Res. Clin. Oncol., 2018, 144(6), 1037-1047.
[] [PMID: 29549529]
McKenney, A.S.; Lau, A.N.; Somasundara, A.V.H.; Spitzer, B.; Intlekofer, A.M.; Ahn, J.; Shank, K.; Rapaport, F.T.; Patel, M.A.; Papalexi, E.; Shih, A.H.; Chiu, A.; Freinkman, E.; Akbay, E.A.; Steadman, M.; Nagaraja, R.; Yen, K.; Teruya-Feldstein, J.; Wong, K.K.; Rampal, R.; Vander Heiden, M.G.; Thompson, C.B.; Levine, R.L. JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J. Clin. Invest., 2018, 128(2), 789-804.
[] [PMID: 29355841]
Pardanani, A.; Lasho, T.L.; Finke, C.M.; Mai, M.; McClure, R.F.; Tefferi, A. IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms. Leukemia, 2010, 24(6), 1146-1151.
[] [PMID: 20410924]
Yen, K.; Travins, J.; Wang, F.; David, M.D.; Artin, E.; Straley, K.; Padyana, A.; Gross, S.; DeLaBarre, B.; Tobin, E.; Chen, Y.; Nagaraja, R.; Choe, S.; Jin, L.; Konteatis, Z.; Cianchetta, G.; Saunders, J.O.; Salituro, F.G.; Quivoron, C.; Opolon, P.; Bawa, O.; Saada, V.; Paci, A.; Broutin, S.; Bernard, O.A.; de Botton, S.; Marteyn, B.S.; Pilichowska, M.; Xu, Y.; Fang, C.; Jiang, F.; Wei, W.; Jin, S.; Silverman, L.; Liu, W.; Yang, H.; Dang, L.; Dorsch, M.; Penard-Lacronique, V.; Biller, S.A.; Su, S.M. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov., 2017, 7(5), 478-493.
[] [PMID: 28193778]
Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; Kantarjian, H.M.; Collins, R.; Patel, M.R.; Frankel, A.E.; Stein, A.; Sekeres, M.A.; Swords, R.T.; Medeiros, B.C.; Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R.D.; Yen, K.E.; Agresta, S.; de Botton, S.; Tallman, M.S. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood, 2017, 130(6), 722-731.
[] [PMID: 28588020]
Stein, E.M. Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. Future Oncol., 2018, 14(1), 23-40.
[] [PMID: 29243965]
Yen, K.; Konteatis, Z.; Sui, Z.; Artin, E.; Dang, L.; Straley, K.; Tobin, E.; Campos, C.; Yang, H.; Nagaraja, R.; Chen, Y.; Kim, H.; Gliser, C.; Nicolay, B.; Olaharski, A.; Silverman, L.; Biller, S.; Su, S.M.; Mellinghoff, I.; Popovici-Muller, J. Abstract B126: AG-881, a brain penetrant, potent, pan-mutant IDH (mIDH) inhibitor for use in mIDH solid and hematologic malignancies. Mol. Cancer Ther., 2018, 17(1)(Suppl.), B126.
Wang, Y; Zhao, L. W.; Liu, X. R.; Zhang, Y.; Huang, D. D.; Jiang, C. H.; Shi, X. S.; Gu, H. F.; Pang, S. L.; Hai, W.; Ge, B. Y. Chemical compound of isocitrate dehydrogenase inhibitor, and application thereof. WO2018014852, 2018.
Konteatis, Z. D.; Popovici-muller, J.; Travins, J. 2,4-4,6- diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer. WO2015006591,, 2015.
Xie, X.; Baird, D.; Bowen, K.; Capka, V.; Chen, J.; Chenail, G.; Cho, Y.; Dooley, J.; Farsidjani, A.; Fortin, P.; Kohls, D.; Kulathila, R.; Lin, F.; McKay, D.; Rodrigues, L.; Sage, D.; Touré, B.B.; van der Plas, S.; Wright, K.; Xu, M.; Yin, H.; Levell, J.; Pagliarini, R.A. Allosteric mutant IDH1 inhibitors reveal mechanisms for IDH1 mutant and isoform selectivity. Structure, 2017, 25(3), 506-513.
[] [PMID: 28132785]
Wang, F.; Travins, J.; DeLaBarre, B.; Penard-Lacronique, V.; Schalm, S.; Hansen, E.; Straley, K.; Kernytsky, A.; Liu, W.; Gliser, C.; Yang, H.; Gross, S.; Artin, E.; Saada, V.; Mylonas, E.; Quivoron, C.; Popovici-Muller, J.; Saunders, J.O.; Salituro, F.G.; Yan, S.; Murray, S.; Wei, W.; Gao, Y.; Dang, L.; Dorsch, M.; Agresta, S.; Schenkein, D.P.; Biller, S.A.; Su, S.M.; de Botton, S.; Yen, K.E. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science, 2013, 340(6132), 622-626.
[] [PMID: 23558173]
Gao, M.; Zhu, H.; Fu, L.; Li, Y.; Bao, X.; Fu, H.; Quan, H.; Wang, L.; Lou, L. Pharmacological characterization of TQ05310, a potent inhibitor of isocitrate dehydrogenase 2 R140Q and R172K mutants. Cancer Sci., 2019, 110(10), 3306-3314.
[] [PMID: 31361380]
Kernytsky, A.; Wang, F.; Hansen, E.; Schalm, S.; Straley, K.; Gliser, C.; Yang, H.; Travins, J.; Murray, S.; Dorsch, M.; Agresta, S.; Schenkein, D.P.; Biller, S.A.; Su, S.M.; Liu, W.; Yen, K.E. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood, 2015, 125(2), 296-303.
[] [PMID: 25398940]
Liu, X.; Gong, Y. Isocitrate dehydrogenase inhibitors in acute myeloid leukemia. Biomark. Res., 2019, 7(1), 22.
[] [PMID: 31660152]
Wang, S. L.; Zhao, N.; Liu, X. J.; Hu, Y. D.; Zhang, H.; Luo, H.; Peng, Y.; Xiao, D. M.; Han, Y. X.; Zhang, X. Q.; Tain, X. Atitumor compound targeting IDH2 mutantion and method of use thereof. WO2017016523,, 2017.
Bauer, R. A.; Boulet, S. L.; Burkholder, T. P.; Gilmour, R.; Hahn, P. J.; Rankovic, Z. 7-PHENYLETHYLAMINO-4HPYRIMIDO[ 4,5-D][1,3]OXAZIN-2-ONE COMPOUNDS AS MUTANT IDH1 AND IDH2 INHIBITORS, WO2018111707,, 2018.
Dinardo, C.D.; Stein, A.S.; Stein, E.M.; Fathi, A.T.; Schuh, A.C.; Montesinos Fernández, P.; Odenike, O.; Kantarjian, H.M.; Stone, R.M.; Collins, R.; Martinelli, G.; Arnan, M.; Wu, B.; Koralek, D.O.; Van Oostendorp, J.; Gong, J.; MacBeth, K.J.; Vyas, P. Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). J. Clin. Oncol., 2018, 36(15), 7042-7042.
Stein, E.M.; DiNardo, C.D.; Fathi, A.T.; Mims, A.S.; Pratz, K.W.; Savona, M.R.; Stein, A.S.; Stone, R.M.; Winer, E.S.; Seet, C.S.; Dohner, H.; Pollyea, D.A.; McCloskey, J.K.; Odenike, O.; Lowenberg, B.; Ossenkoppele, G.J.; Patel, P.A.; Roshal, M.; Lersch, F.; Nabhan, S.; Choe, S.; Wang, H.F.; Hua, L.; Almon, C.; Cooper, M.; Tallman, M.S. Ivosidenib or enasidenib combined with induction and consolidation chemotherapy in patients with newly diagnosed AML with an IDH1 or IDH2 mutation is safe, effective, and leads to MRD-negative complete remissions. Blood, 2018, 132, 5.
Hotchkiss, R.S.; Strasser, A.; McDunn, J.E.; Swanson, P.E. Cell death. N. Engl. J. Med., 2009, 361(16), 1570-1583.
[] [PMID: 19828534]
Tiong, I.S.; Wei, A.H. New drugs creating new challenges in acute myeloid leukemia. Genes Chromosomes Cancer, 2019, 58(12), 903-914.
[] [PMID: 30861214]
Amatangelo, M.D.; Quek, L.; Shih, A.; Stein, E.M.; Roshal, M.; David, M.D.; Marteyn, B.; Farnoud, N.R.; de Botton, S.; Bernard, O.A.; Wu, B.; Yen, K.E.; Tallman, M.S.; Papaemmanuil, E.; Penard-Lacronique, V.; Thakurta, A.; Vyas, P.; Levine, R.L. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood, 2017, 130(6), 732-741.
[] [PMID: 28588019]
Quek, L.; David, M.D.; Kennedy, A.; Metzner, M.; Amatangelo, M.; Shih, A.; Stoilova, B.; Quivoron, C.; Heiblig, M.; Willekens, C.; Saada, V.; Alsafadi, S.; Vijayabaskar, M.S.; Peniket, A.; Bernard, O.A.; Agresta, S.; Yen, K.; MacBeth, K.; Stein, E.; Vassiliou, G.S.; Levine, R.; De Botton, S.; Thakurta, A.; Penard-Lacronique, V.; Vyas, P. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat. Med., 2018, 24(8), 1167-1177.
[] [PMID: 30013198]
Intlekofer, A.M.; Shih, A.H.; Wang, B.; Nazir, A.; Rustenburg, A.S.; Albanese, S.K.; Patel, M.; Famulare, C.; Correa, F.M.; Takemoto, N.; Durani, V.; Liu, H.; Taylor, J.; Farnoud, N.; Papaemmanuil, E.; Cross, J.R.; Tallman, M.S.; Arcila, M.E.; Roshal, M.; Petsko, G.A.; Wu, B.; Choe, S.; Konteatis, Z.D.; Biller, S.A.; Chodera, J.D.; Thompson, C.B.; Levine, R.L.; Stein, E.M. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature, 2018, 559(7712), 125-129.
[] [PMID: 29950729]
Sun, X.J.; Chen, S.J.; Chen, Z. Treating leukemia: Differentiation therapy for mIDH2 AML. Cell Res., 2019, 29(6), 427-428.
[] [PMID: 31086254]
Bjørklund, G.; Aaseth, J.; Dadar, M.; Butnariu, M.; Chirumbolo, S. Exposure to environmental organic mercury and impairments in human fertility. J. Reprod. Infertil.,, 2019, 20(3), 195-197.
[PMID: 31423423]
Ajsuvakova, O.P.; Tinkov, A.A.; Aschner, M.; Rocha, J.B.T.; Michalke, B.; Skalnaya, M.G.; Skalny, A.V.; Butnariu, M.; Dadar, M.; Sarac, I.; Aaseth, J.; Bjorklund, G. Sulfhydryl groups as targets of mercury toxicity. Coordin. Chem. Rev., 2020, 417.,
Bjørklund, G.; Chirumbolo, S.; Dadar, M.; Pivina, L.; Lindh, U.; Butnariu, M.; Aaseth, J. Mercury exposure and its effects on fertility and pregnancy outcome. Basic Clin. Pharmacol. Toxicol., 2019, 125(4), 317-327.
[] [PMID: 31136080]
Hassan, F.; El-Hiti, G.A.; Abd-Allateef, M.; Yousif, E. Cytotoxicity anticancer activities of anastrozole against breast, liver hepatocellular, and prostate cancer cells. Saudi Med. J., 2017, 38(4), 359-365.
[] [PMID: 28397941]
Hassan, F.; Hameed, A.A.; Alshanon, A.; Abdullah, B.M.; Huri, H.Z.; Hairunisa, N.; Yousif, E. Antitumor activity for gold (III) complex by high content screening technique (HCS) and cell viability assay. Asian J. Biochem., 2015, 10(6), 252-266.

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