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

Janeta Popovici-Muller; Jeffrey O Saunders; Francesco G Salituro; Jeremy M Travins; Shunqi Yan; Fang Zhao; Stefan Gross; Lenny Dang; Katharine E Yen; Hua Yang; Kimberly S Straley; Shengfang Jin; Kaiko Kunii; Valeria R Fantin; Shunan Zhang; Qiongqun Pan; Derek Shi; Scott A Biller; Shinsan M Su

doi:10.1021/ml300225h

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

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

Authors

Janeta Popovici-Muller¹, Jeffrey O Saunders², Francesco G Salituro³, Jeremy M Travins¹, Shunqi Yan⁴, Fang Zhao⁵, Stefan Gross¹, Lenny Dang¹, Katharine E Yen¹, Hua Yang¹, Kimberly S Straley¹, Shengfang Jin¹, Kaiko Kunii¹, Valeria R Fantin⁶, Shunan Zhang⁷, Qiongqun Pan⁷, Derek Shi⁷, Scott A Biller¹, Shinsan M Su¹

Affiliations

¹ Agios Pharmaceuticals , 38 Sidney Street, Cambridge, Massachusetts 02139, United States.
² Ember Therapeutics , 855 Boylston Street, 11th Floor, Suite B, Boston, Massachusetts 02116, United States.
³ Sage Therapeutics , 215 First Street, Cambridge, Massachusetts 02141, United States.
⁴ Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
⁵ Sundia MediTech Company, Ltd. , Building 8, 388 Jialilue Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
⁶ Oncology Research Unit, Pfizer Worldwide Research and Development , La Jolla Laboratories, San Diego, California 92121, United States.
⁷ Shanghai ChemPartner Co., LTD , 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China.

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.

Keywords: Mutant IDH1; R132H IDH1 inhibitors; tumor 2-HG.