Figure 12.

Structure of aminotriazine-based inhibitors and their interaction with IDH1_R132H and IDH2_R140Q. (A) Structure of preclinical and clinical mIDH1/2-selective inhibitors with an aminotriazine backbone (indicated in blue) [87,88]. (B) Scheme illustrating inhibitor-protein interactions in the crystal structures of AG-881 in complex with IDH1_R132H (left, PDB: 6VEI) or IDH2_R140Q (right, PDB: 6VFZ) homodimers. Amino acid residues that directly interact with the inhibitors are shown in orange circles, with dotted circles indicating residues belonging to the second monomer and dotted lines indicating the formation of hydrogen (orange) or halogen (green) bonds, respectively. In addition, key hydrophobic interactions of the inhibitors with the protein are indicated in turquoise. (C) Structure of the only radiolabeled analog of the inhibitors shown in A that has been described, with the radiolabel indicated in red [61].