title: Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo.
abstract: Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.affiliation: Ember Therapeutics , 855 Boylston Street, 11th Floor, Suite B, Boston, Massachusetts 02116, United States.
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
authors.affiliation: Sage Therapeutics , 215 First Street, Cambridge, Massachusetts 02141, United States.
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Travins
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.affiliation: Sundia MediTech Company, Ltd. , Building 8, 388 Jialilue Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.affiliation: Oncology Research Unit, Pfizer Worldwide Research and Development , La Jolla Laboratories, San Diego, California 92121, United States.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.affiliation: Shanghai ChemPartner Co., LTD , 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Shunan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Shanghai ChemPartner Co., LTD , 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Qiongqun
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Shanghai ChemPartner Co., LTD , 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.
authors.forename: Derek
authors.initials: D
authors.lastname: Shi
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.affiliation: Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
keywords: Mutant IDH1; R132H IDH1 inhibitors; tumor 2-HG