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ACS Med Chem Lett. 2012 Sep 17;3(10):850-5. doi: 10.1021/ml300225h. eCollection 2012 Oct 11.

Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo.

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Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
Ember Therapeutics , 855 Boylston Street, 11th Floor, Suite B, Boston, Massachusetts 02116, United States.
Sage Therapeutics , 215 First Street, Cambridge, Massachusetts 02141, United States.
Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
Sundia MediTech Company, Ltd. , Building 8, 388 Jialilue Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
Oncology Research Unit, Pfizer Worldwide Research and Development , La Jolla Laboratories, San Diego, California 92121, United States.
Shanghai ChemPartner Co., LTD , 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.


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.


Mutant IDH1; R132H IDH1 inhibitors; tumor 2-HG

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