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.
Janeta Popovici-Muller  1 ,  Jeffrey O Saunders  2 ,  Francesco G Salituro  3 ,  Jeremy M Travins  1 ,  Shunqi Yan  4 ,  Fang Zhao  5 ,  Stefan Gross  1 ,  Lenny Dang  1 ,  Katharine E Yen  1 ,  Hua Yang  1 ,  Kimberly S Straley  1 ,  Shengfang Jin  1 ,  Kaiko Kunii  1 ,  Valeria R Fantin  6 ,  Shunan Zhang  7 ,  Qiongqun Pan  7 ,  Derek Shi  7 ,  Scott A Biller  1 ,  Shinsan M Su  1
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.
PMID: 24900389 DOI: 10.1021/ml300225h
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.