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

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

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.

Figures