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. 2020 Jan 22;11(2):101-107.
doi: 10.1021/acsmedchemlett.9b00509. eCollection 2020 Feb 13.

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

Zenon Konteatis  1 , Erin Artin  1 , Brandon Nicolay  1 , Kimberly Straley  1 , Anil K Padyana  1 , Lei Jin  1 , Yue Chen  1 , Rohini Narayaraswamy  1 , Shuilong Tong  2 , Feng Wang  3 , Ding Zhou  4 , Dawei Cui  4 , Zhenwei Cai  4 , Zhiyong Luo  5 , Cheng Fang  5 , Huachun Tang  5 , Xiaobing Lv  5 , Raj Nagaraja  1 , Hua Yang  1 , Shin-San M Su  1 , Zhihua Sui  1 , Lenny Dang  1 , Katharine Yen  1 , Janeta Popovici-Muller  1 , Paolo Codega  6 , Carl Campos  6 , Ingo K Mellinghoff  6 , Scott A Biller  1
Affiliations

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

Zenon Konteatis et al. ACS Med Chem Lett. .

Abstract

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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Conflict of interest statement

The authors declare the following competing financial interest(s): All Agios authors were employees and stockholders at the time of the study.

Figures

Figure 1
Figure 1
(A) Cocrystal structure of AGI-15056 in complex with IDH1-R132H homodimer. mIDH1 is in the inhibitory open homodimer conformation. (B) Close-up of the allosteric site; helix 9’ has been removed for clarity. AGI-15056 shows two possible pseudosymmetric binding conformations. Abbreviations: IDH, isocitrate dehydrogenase; mIDH, mutant isocitrate dehydrogenase.
Figure 2
Figure 2
Cocrystal structure of vorasidenib in complex with (A) IDH1-R132H with a single conformation fit and (B) IDH2-R140Q with two alternate conformation fits. The electron density around vorasidenib is contoured at 1.0σ using a 2mFo-DFc map shown as a surface envelope along with the polar interactions to the binding site residues shown as dashed lines. Abbreviation: IDH, isocitrate dehydrogenase.
Figure 3
Figure 3
Vorasidenib concentrations in plasma, brain, and cerebrospinal fluid (3 mg/kg single oral dose in rats; n = 3).
Figure 4
Figure 4
Vorasidenib (AG-881) inhibited 2-HG levels in an orthotopic grade III mIDH1 glioma model derived from the TS603 neurosphere. Dose: 50 mg/kg by mouth twice daily for 4 days. aGrayed area represents the dose interval; the 24-h time point was included to assess how long 2-HG inhibition was sustained in the brain tumor after the last dose. %2-HG inhibition was established after subtracting 2-HG AUC0–12h of “normal” brain (observed in left hemisphere of brains in all animals), from brain tumor AUC0–12h. Gray dashed line represents the 2-HG concentrations in the brain tumors of untreated animals. Abbreviations: 2-HG, d-2-hydroxyglutarate; AUC0–12h, area under the curve from 0 to 12 h; mIDH, mutant isocitrate dehydrogenase.
See this image and copyright information in PMC

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