Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma

[Image: see text] Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe...

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Autores principales: Konteatis, Zenon, Artin, Erin, Nicolay, Brandon, Straley, Kimberly, Padyana, Anil K., Jin, Lei, Chen, Yue, Narayaraswamy, Rohini, Tong, Shuilong, Wang, Feng, Zhou, Ding, Cui, Dawei, Cai, Zhenwei, Luo, Zhiyong, Fang, Cheng, Tang, Huachun, Lv, Xiaobing, Nagaraja, Raj, Yang, Hua, Su, Shin-San M., Sui, Zhihua, Dang, Lenny, Yen, Katharine, Popovici-Muller, Janeta, Codega, Paolo, Campos, Carl, Mellinghoff, Ingo K., Biller, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025383/
https://www.ncbi.nlm.nih.gov/pubmed/32071674
http://dx.doi.org/10.1021/acsmedchemlett.9b00509
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author Konteatis, Zenon
Artin, Erin
Nicolay, Brandon
Straley, Kimberly
Padyana, Anil K.
Jin, Lei
Chen, Yue
Narayaraswamy, Rohini
Tong, Shuilong
Wang, Feng
Zhou, Ding
Cui, Dawei
Cai, Zhenwei
Luo, Zhiyong
Fang, Cheng
Tang, Huachun
Lv, Xiaobing
Nagaraja, Raj
Yang, Hua
Su, Shin-San M.
Sui, Zhihua
Dang, Lenny
Yen, Katharine
Popovici-Muller, Janeta
Codega, Paolo
Campos, Carl
Mellinghoff, Ingo K.
Biller, Scott A.
author_facet Konteatis, Zenon
Artin, Erin
Nicolay, Brandon
Straley, Kimberly
Padyana, Anil K.
Jin, Lei
Chen, Yue
Narayaraswamy, Rohini
Tong, Shuilong
Wang, Feng
Zhou, Ding
Cui, Dawei
Cai, Zhenwei
Luo, Zhiyong
Fang, Cheng
Tang, Huachun
Lv, Xiaobing
Nagaraja, Raj
Yang, Hua
Su, Shin-San M.
Sui, Zhihua
Dang, Lenny
Yen, Katharine
Popovici-Muller, Janeta
Codega, Paolo
Campos, Carl
Mellinghoff, Ingo K.
Biller, Scott A.
author_sort Konteatis, Zenon
collection PubMed
description [Image: see text] Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.
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spelling pubmed-70253832020-02-18 Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma Konteatis, Zenon Artin, Erin Nicolay, Brandon Straley, Kimberly Padyana, Anil K. Jin, Lei Chen, Yue Narayaraswamy, Rohini Tong, Shuilong Wang, Feng Zhou, Ding Cui, Dawei Cai, Zhenwei Luo, Zhiyong Fang, Cheng Tang, Huachun Lv, Xiaobing Nagaraja, Raj Yang, Hua Su, Shin-San M. Sui, Zhihua Dang, Lenny Yen, Katharine Popovici-Muller, Janeta Codega, Paolo Campos, Carl Mellinghoff, Ingo K. Biller, Scott A. ACS Med Chem Lett [Image: see text] Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma. American Chemical Society 2020-01-22 /pmc/articles/PMC7025383/ /pubmed/32071674 http://dx.doi.org/10.1021/acsmedchemlett.9b00509 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Konteatis, Zenon
Artin, Erin
Nicolay, Brandon
Straley, Kimberly
Padyana, Anil K.
Jin, Lei
Chen, Yue
Narayaraswamy, Rohini
Tong, Shuilong
Wang, Feng
Zhou, Ding
Cui, Dawei
Cai, Zhenwei
Luo, Zhiyong
Fang, Cheng
Tang, Huachun
Lv, Xiaobing
Nagaraja, Raj
Yang, Hua
Su, Shin-San M.
Sui, Zhihua
Dang, Lenny
Yen, Katharine
Popovici-Muller, Janeta
Codega, Paolo
Campos, Carl
Mellinghoff, Ingo K.
Biller, Scott A.
Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title_full Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title_fullStr Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title_full_unstemmed Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title_short Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
title_sort vorasidenib (ag-881): a first-in-class, brain-penetrant dual inhibitor of mutant idh1 and 2 for treatment of glioma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025383/
https://www.ncbi.nlm.nih.gov/pubmed/32071674
http://dx.doi.org/10.1021/acsmedchemlett.9b00509
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