IC50:< 100 nM

AG-120 is an IDH1 inhibitor.

Isocitrate dehydrogenase (IDH) is a metabolic enzyme interconverting isocitrate and α-ketoglutarate (α-KG), but cancer-associated mutations of IDH1 and IDH2 confer a neomorphic activity, which allows reduction of α-KG to the oncometabolite 2-HG.

In vitro: TF-1 cells or primary human AML patient samples expressing mutant IDH1 were treated with AG-120, and the results showed that in TF-1 IDH1-R132H cells, AG-120 was able to decrease the intracellular 2-HG levels, inhibit growth factor independent proliferation and restore erythropoietin-induced differentiation [1].

Ex vivo: Previous ex-vivo study showed that the pharmacological inhibition of mutant IDH1 enzyme with AG-120 in primary human blast cells led to an effective way to lower intracellular 2-HG levels and induced myeloid differentiation [1].

Clinical trial: In a phase I clinical trial, 62 patients with advanced IDH1 mutation–positive solid tumors were treated with single agent AG-120 orally once a day. Results showed that 7 of 11 patients with IDH1 mutant–positive chondrosarcoma had stable disease; 1 out of 20 patients with IDH1 mutant–positive IHCC had a partial response and 11 patients had SD; and one out of four patients with other IDH1 mutant–positive solid tumors had SD [2].

References:
[1] Erica Hansen et al.  AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient Samples Treated Ex Vivo. Blood 2014 124:3734.
[2] http://www. aacr.org/Newsroom/Pages/News-Release-Detail.aspx ItemID=789#.WLAUOm997IU