Search

Supplementary Figure 1. Synthesis and pharmacokinetic characterization of AG-221. Supplementary Figure 2. Biochemical attributes of AG-221. Supplementary Figure 3. Biochemistry of AG-221 with respect to substrate and cofactor. Supplementary Figure 4. TF-1 IDH2R140Q cells treated with AG-221. Supplementary Figure 5. AG-221 can reverse the block in EPO-induced differentiation caused by the expression of IDH2R140Q in the TF-1 erythroleukemia cell line. Supplementary Figure 6. Pharmacokinetics/pharmacodynamics of AG-221 in IDH2R140Qmutant U87MG xenograft tumor-bearing mice. Supplementary Figure 7. AG-221 does not affect intrinsic hematological parameters or body weight. Supplementary Figure 8. AG-221 strongly reduces the number of human IDH2R140Q blasts in the liver and spleen in AML-1, AML-2, and AML-3. Supplementary Figure 9. Flow cytometry analyses of bone marrow-derived hCD45+ cells in primary human AML xenograft models. Supplementary Figure 10. Affinity of the IDH2R140Q homodimer for NADPH. Supplementary Figure 11. Electron density map diagrams for bound ligands for IDH2R140Q co-complex structures determined by X-ray crystallography.

Supplementary Table 1. Drug metabolism and pharmacokinetic attributes of AG-221. Supplementary Table 2. Selectivity of AG-221 confirmed by testing against a panel of kinases. Supplementary Table 3. Clinical characteristics of patients with IDH2R140Q-mutated AML. Supplementary Table 4. Treated NSG mice (AML-1, AML-2, AML-3) engrafted with human IDH2R140Q mononuclear cells display stable levels of AG-221 in serum. Supplementary Table 5. AG-221 inhibits 2HG production in models AML-1, AML-2, and AML-3. Supplementary Table 6. Summary of pharmacokinetics/pharmacodynamics in primary human acute myeloid leukemia xenograft model (AML-4). Supplementary Table 7. Summary of data collection and refinement statistics. Supplementary Table 8. Percentage of human chimerism in peripheral blood in models AML-1 and AML-2.

Supplementary Methods

AG-221 or enasidenib is a first-in-class selective inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) with early demonstrated clinical efficacy in acute myeloid leukemia as a single agent, yet with persistence of mutant IDH2 clones. Two papers in this issue of Cancer Discovery provide further insight into the biological activity of AG-221 in promoting differentiation of IDH2 mutant cells and reversing aberrant DNA methylation over time, and demonstrating pre-clinical activity in combination with a targeted FLT3 kinase inhibitor to eliminate IDH2 mutant clones.