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

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

doi:10.1021/acsmedchemlett.7b00421

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

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

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

332 Citations (Scopus)

Résumé

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.

langue originale	Anglais
Pages (de - à)	300-305
Nombre de pages	6
journal	ACS Medicinal Chemistry Letters
Volume	9
Numéro de publication	4
Les DOIs	https://doi.org/10.1021/acsmedchemlett.7b00421
état	Publié - 12 avr. 2018
Modification externe	Oui

Accès au document

10.1021/acsmedchemlett.7b00421

Autres fichiers et liens

Lien vers la publication dans Scopus

Contient cette citation

Popovici-Muller, J., Lemieux, R. M., Artin, E., Saunders, J. O., Salituro, F. G., Travins, J., Cianchetta, G., Cai, Z., Zhou, D., Cui, D., Chen, P., Straley, K., Tobin, E., Wang, F., David, M. D., Penard-Lacronique, V., Quivoron, C., Saada, V., De Botton, S., ... Yen, K. (2018). Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Medicinal Chemistry Letters, 9(4), 300-305. https://doi.org/10.1021/acsmedchemlett.7b00421

@article{b264bb6f4efd4051bfb8b0830dc38985,

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

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.",

keywords = "2-hydroxyglutarate, AG-120, differentiation therapy, isocitrate dehydrogenase, ivosidenib, mutant IDH1",

author = "Janeta Popovici-Muller and Lemieux, {Ren{\'e} M.} and Erin Artin and Saunders, {Jeffrey O.} and Salituro, {Francesco G.} and Jeremy Travins and Giovanni Cianchetta and Zhenwei Cai and Ding Zhou and Dawei Cui and Ping Chen and Kimberly Straley and Erica Tobin and Fang Wang and David, {Muriel D.} and Virginie Penard-Lacronique and Cyril Quivoron and V{\'e}ronique Saada and {De Botton}, St{\'e}phane and Stefan Gross and Lenny Dang and Hua Yang and Luke Utley and Yue Chen and Hyeryun Kim and Shengfang Jin and Zhiwei Gu and Gui Yao and Zhiyong Luo and Xiaobing Lv and Cheng Fang and Liping Yan and Andrew Olaharski and Lee Silverman and Scott Biller and Su, {Shin San M.} and Katharine Yen",

note = "Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = apr,

day = "12",

doi = "10.1021/acsmedchemlett.7b00421",

language = "English",

volume = "9",

pages = "300--305",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

number = "4",

}

Popovici-Muller, J, Lemieux, RM, Artin, E, Saunders, JO, Salituro, FG, Travins, J, Cianchetta, G, Cai, Z, Zhou, D, Cui, D, Chen, P, Straley, K, Tobin, E, Wang, F, David, MD, Penard-Lacronique, V, Quivoron, C, Saada, V, De Botton, S, Gross, S, Dang, L, Yang, H, Utley, L, Chen, Y, Kim, H, Jin, S, Gu, Z, Yao, G, Luo, Z, Lv, X, Fang, C, Yan, L, Olaharski, A, Silverman, L, Biller, S, Su, SSM & Yen, K 2018, 'Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers', ACS Medicinal Chemistry Letters, VOL. 9, Numéro 4, p. 300-305. https://doi.org/10.1021/acsmedchemlett.7b00421

TY - JOUR

T1 - Discovery of AG-120 (Ivosidenib)

T2 - A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

AU - Popovici-Muller, Janeta

AU - Lemieux, René M.

AU - Artin, Erin

AU - Saunders, Jeffrey O.

AU - Salituro, Francesco G.

AU - Travins, Jeremy

AU - Cianchetta, Giovanni

AU - Cai, Zhenwei

AU - Zhou, Ding

AU - Cui, Dawei

AU - Chen, Ping

AU - Straley, Kimberly

AU - Tobin, Erica

AU - Wang, Fang

AU - David, Muriel D.

AU - Penard-Lacronique, Virginie

AU - Quivoron, Cyril

AU - Saada, Véronique

AU - De Botton, Stéphane

AU - Gross, Stefan

AU - Dang, Lenny

AU - Yang, Hua

AU - Utley, Luke

AU - Chen, Yue

AU - Kim, Hyeryun

AU - Jin, Shengfang

AU - Gu, Zhiwei

AU - Yao, Gui

AU - Luo, Zhiyong

AU - Lv, Xiaobing

AU - Fang, Cheng

AU - Yan, Liping

AU - Olaharski, Andrew

AU - Silverman, Lee

AU - Biller, Scott

AU - Su, Shin San M.

AU - Yen, Katharine

PY - 2018/4/12

Y1 - 2018/4/12

N2 - 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.

AB - 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.

KW - 2-hydroxyglutarate

KW - AG-120

KW - differentiation therapy

KW - isocitrate dehydrogenase

KW - ivosidenib

KW - mutant IDH1

UR - http://www.scopus.com/inward/record.url?scp=85045384985&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.7b00421

DO - 10.1021/acsmedchemlett.7b00421

M3 - Article

AN - SCOPUS:85045384985

SN - 1948-5875

VL - 9

SP - 300

EP - 305

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -