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Brain cancer

Isocitrate dehydrogenase 1 (IDH1)

Mouse and in vitro studies suggest inhibiting mutant IDH1 could help treat IDH1-mutant gliomas. In vitro, AGI-5198 inhibited mutant IDH1 with an IC50 value of 70 nM without also inhibiting wild-type IDH1 at detectable levels. In a mouse xenograft model for human glioma, AGI-5198 decreased levels of the (R)-enantiomer of 2-hydroxyglutarate (2-HG), an oncometabolite specifically produced by the mutant enzyme, and decreased tumor growth compared with vehicle. Next steps include conducting further preclinical development of mutant-selective IDH1 inhibitors and testing the effects of the inhibitors in other IDH1-mutant solid tumors.
Agios Pharmaceuticals Inc. has preclinical programs targeting IDH1 and IDH2 in cancers with mutations in the metabolic enzymes (see Oncometabolite takedown, page 7).

SciBX 6(14); doi:10.1038/scibx.2013.332
Published online April 11, 2013

Patent applications filed; partnered with Celgene Corp.

Rohle, D. et al. Science; published online April 4, 2013;
Contact: Katharine E. Yen, Agios Pharmaceuticals Inc., Cambridge, Mass.

Contact: Ingo K. Mellinghoff, Memorial Sloan-Kettering Cancer Center, New York, N.Y.