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New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

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New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. / 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, Iléana; 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.

in: NAT CHEM BIOL, Jahrgang 11, Nr. 11, 11.2015, S. 878-86.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Okoye-Okafor, UC, Bartholdy, B, Cartier, J, Gao, EN, Pietrak, B, Rendina, AR, Rominger, C, Quinn, C, Smallwood, A, Wiggall, KJ, Reif, AJ, Schmidt, SJ, Qi, H, Zhao, H, Joberty, G, Faelth-Savitski, M, Bantscheff, M, Drewes, G, Duraiswami, C, Brady, P, Groy, A, Narayanagari, S-R, Antony-Debre, I, Mitchell, K, Wang, HR, Kao, Y-R, Christopeit, M, Carvajal, L, Barreyro, L, Paietta, E, Makishima, H, Will, B, Concha, N, Adams, ND, Schwartz, B, McCabe, MT, Maciejewski, J, Verma, A & Steidl, U 2015, 'New IDH1 mutant inhibitors for treatment of acute myeloid leukemia', NAT CHEM BIOL, Jg. 11, Nr. 11, S. 878-86. https://doi.org/10.1038/nchembio.1930

APA

Okoye-Okafor, U. C., Bartholdy, B., Cartier, J., Gao, E. N., Pietrak, B., Rendina, A. R., Rominger, C., Quinn, C., Smallwood, A., Wiggall, K. J., Reif, A. J., Schmidt, S. J., Qi, H., Zhao, H., Joberty, G., Faelth-Savitski, M., Bantscheff, M., Drewes, G., Duraiswami, C., ... Steidl, U. (2015). New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. NAT CHEM BIOL, 11(11), 878-86. https://doi.org/10.1038/nchembio.1930

Vancouver

Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. NAT CHEM BIOL. 2015 Nov;11(11):878-86. https://doi.org/10.1038/nchembio.1930

Bibtex

@article{0faf6256459849a9981e6441aafc32fe,
title = "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.",
author = "Okoye-Okafor, {Ujunwa C} and Boris Bartholdy and Jessy Cartier and Gao, {Enoch N} and Beth Pietrak and Rendina, {Alan R} and Cynthia Rominger and Chad Quinn and Angela Smallwood and Wiggall, {Kenneth J} and Reif, {Alexander J} and Schmidt, {Stanley J} and Hongwei Qi and Huizhen Zhao and Gerard Joberty and Maria Faelth-Savitski and Marcus Bantscheff and Gerard Drewes and Chaya Duraiswami and Pat Brady and Arthur Groy and Swathi-Rao Narayanagari and Il{\'e}ana Antony-Debre and Kelly Mitchell and Wang, {Heng Rui} and Yun-Ruei Kao and Maximilian Christopeit and Luis Carvajal and Laura Barreyro and Elisabeth Paietta and Hideki Makishima and Britta Will and Nestor Concha and Adams, {Nicholas D} and Benjamin Schwartz and McCabe, {Michael T} and Jaroslav Maciejewski and Amit Verma and Ulrich Steidl",
year = "2015",
month = nov,
doi = "10.1038/nchembio.1930",
language = "English",
volume = "11",
pages = "878--86",
journal = "NAT CHEM BIOL",
issn = "1552-4450",
publisher = "NATURE PUBLISHING GROUP",
number = "11",

}

RIS

TY - JOUR

T1 - New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

AU - Okoye-Okafor, Ujunwa C

AU - Bartholdy, Boris

AU - Cartier, Jessy

AU - Gao, Enoch N

AU - Pietrak, Beth

AU - Rendina, Alan R

AU - Rominger, Cynthia

AU - Quinn, Chad

AU - Smallwood, Angela

AU - Wiggall, Kenneth J

AU - Reif, Alexander J

AU - Schmidt, Stanley J

AU - Qi, Hongwei

AU - Zhao, Huizhen

AU - Joberty, Gerard

AU - Faelth-Savitski, Maria

AU - Bantscheff, Marcus

AU - Drewes, Gerard

AU - Duraiswami, Chaya

AU - Brady, Pat

AU - Groy, Arthur

AU - Narayanagari, Swathi-Rao

AU - Antony-Debre, Iléana

AU - Mitchell, Kelly

AU - Wang, Heng Rui

AU - Kao, Yun-Ruei

AU - Christopeit, Maximilian

AU - Carvajal, Luis

AU - Barreyro, Laura

AU - Paietta, Elisabeth

AU - Makishima, Hideki

AU - Will, Britta

AU - Concha, Nestor

AU - Adams, Nicholas D

AU - Schwartz, Benjamin

AU - McCabe, Michael T

AU - Maciejewski, Jaroslav

AU - Verma, Amit

AU - Steidl, Ulrich

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

U2 - 10.1038/nchembio.1930

DO - 10.1038/nchembio.1930

M3 - SCORING: Journal article

C2 - 26436839

VL - 11

SP - 878

EP - 886

JO - NAT CHEM BIOL

JF - NAT CHEM BIOL

SN - 1552-4450

IS - 11

ER -