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

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 xe...

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Published inACS medicinal chemistry letters Vol. 3; no. 10; pp. 850 - 855
Main Authors Popovici-Muller, Janeta, Saunders, Jeffrey O, Salituro, Francesco G, Travins, Jeremy M, Yan, Shunqi, Zhao, Fang, Gross, Stefan, Dang, Lenny, Yen, Katharine E, Yang, Hua, Straley, Kimberly S, Jin, Shengfang, Kunii, Kaiko, Fantin, Valeria R, Zhang, Shunan, Pan, Qiongqun, Shi, Derek, Biller, Scott A, Su, Shinsan M
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 11.10.2012
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
R132H IDH1 inhibitors
Mutant IDH1
tumor 2-HG
GLIOMAS
MUTATIONS
DIFFERENTIATION
ONCOMETABOLITE 2-HYDROXYGLUTARATE
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Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1948-5875
1948-5875
DOI:10.1021/ml300225h