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

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.

SUBMITTER: Popovici-Muller J

PROVIDER: S-EPMC4025665 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Popovici-Muller Janeta J Saunders Jeffrey O JO Salituro Francesco G FG Travins Jeremy M JM Yan Shunqi S Zhao Fang F Gross Stefan S Dang Lenny L Yen Katharine E KE Yang Hua H Straley Kimberly S KS Jin Shengfang S Kunii Kaiko K Fantin Valeria R VR Zhang Shunan S Pan Qiongqun Q Shi Derek D Biller Scott A SA Su Shinsan M SM

ACS medicinal chemistry letters 20120917 10

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. ...[more]

PMID: 24900389

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