Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jan 19;9(4):300-305.
doi: 10.1021/acsmedchemlett.7b00421. eCollection 2018 Apr 12.

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

Janeta Popovici-Muller  1 , René M Lemieux  1 , Erin Artin  1 , Jeffrey O Saunders  1 , Francesco G Salituro  1 , Jeremy Travins  1 , Giovanni Cianchetta  1 , Zhenwei Cai  2 , Ding Zhou  2 , Dawei Cui  2 , Ping Chen  2 , Kimberly Straley  1 , Erica Tobin  1 , Fang Wang  1 , Muriel D David  3 , Virginie Penard-Lacronique  3 , Cyril Quivoron  3 , Véronique Saada  3 , Stéphane de Botton  3 , Stefan Gross  1 , Lenny Dang  1 , Hua Yang  1 , Luke Utley  1 , Yue Chen  1 , Hyeryun Kim  1 , Shengfang Jin  1 , Zhiwei Gu  4 , Gui Yao  4 , Zhiyong Luo  4 , Xiaobing Lv  4 , Cheng Fang  4 , Liping Yan  4 , Andrew Olaharski  1 , Lee Silverman  1 , Scott Biller  1 , Shin-San M Su  1 , Katharine Yen  1
Affiliations

Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

Janeta Popovici-Muller et al. ACS Med Chem Lett. .

Abstract

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): S.d.B. serves on advisory boards for Agios and Celgene. S.S.M.S is a consultant for Agios.

Figures

Figure 1
Figure 1
Mean ± SD concentrations of AG-120 in plasma and 2-HG in tumor after single oral administration of AG-120 at 50 or 150 mg/kg in a mouse HT1080 xenograft tumor model (n = 3 at each time point).
Figure 2
Figure 2
Percent intracellular 2-HG remaining relative to DMSO control after 6 days’ treatment with AG-120 in mIDH1-R132H or mIDH1-R132C patient samples (mean ± SEM from cells from four patients with mIDH1 AML).
See this image and copyright information in PMC

References

    1. Dang L.; Su S. M. Isocitrate Dehydrogenase Mutation and (R)-2-Hydroxyglutarate: From Basic Discovery to Therapeutics Development. Annu. Rev. Biochem. 2017, 86, 305–331. 10.1146/annurev-biochem-061516-044732. - DOI - PubMed
    1. 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. 10.1038/nature08617. - DOI - PMC - PubMed
    1. 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.; Lowenberg B.; Licht J. D.; Godley L. A.; Delwel R.; Valk P. J.; 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. 10.1016/j.ccr.2010.11.015. - DOI - PMC - PubMed
    1. Lu C.; Ward P. S.; Kapoor G. S.; Rohle D.; Turcan S.; Abdel-Wahab O.; Edwards C. R.; Khanin R.; Figueroa M. E.; Melnick A.; Wellen K. E.; O’Rourke D. M.; Berger S. L.; Chan T. A.; Levine R. L.; Mellinghoff I. K.; Thompson C. B. IDH Mutation Impairs Histone Demethylation and Results in a Block to Cell Differentiation. Nature 2012, 483 (7390), 474–478. 10.1038/nature10860. - DOI - PMC - PubMed
    1. Rohle D.; Popovici-Muller J.; Palaskas N.; Turcan S.; Grommes C.; Campos C.; Tsoi J.; Clark O.; Oldrini B.; Komisopoulou E.; Kunii K.; Pedraza A.; Schalm S.; Silverman L.; Miller A.; Wang F.; Yang H.; Chen Y.; Kernytsky A.; Rosenblum M. K.; Liu W.; Biller S. A.; Su S. M.; Brennan C. W.; Chan T. A.; Graeber T. G.; Yen K. E.; Mellinghoff I. K. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. Science 2013, 340 (6132), 626–630. 10.1126/science.1236062. - DOI - PMC - PubMed