Somatic point mutations at a key arginine residue (R132) within the active site 
of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of 
function in cancer cells, resulting in the production of d-2-hydroxyglutarate 
(2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic 
alterations and impaired cellular differentiation. IDH1 mutations have been 
described in an array of hematologic malignancies and solid tumors. Here, we 
report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant 
enzyme that exhibits profound 2-HG lowering in tumor models and the ability to 
effect differentiation of primary patient AML samples ex vivo. Preliminary data 
from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 
mutation indicate that AG-120 has an acceptable safety profile and clinical 
activity.