Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia

Abstract

Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

Keywords: 2-hydroxyglutarate; Alpha-ketoglutarate; Isocitrate dehydrogenase; Mutant IDH1.

Fig. 1

Molecular structure of olutasidenib and ivosidenib. (left) Olutasidenib has a chemical formula of C₁₈H₁₅CIN₄O₂. The molecular weight of olutasidenib is 355 g/mol. (right) Ivosidenib has a chemical formula of C₂₈H₂₂CIF₃N₅O₃. The molecular weight of ivosidenib is 583 g/mol

Fig. 2

Reactions catalyzed by wild-type and mutant IDH1. Wild-type IDH1 (w.t. IDH1) converts isocitrate to α-ketoglutarate (α-KG) in a reaction that uses NADP + as an electron acceptor and produces NADPH. A point mutation in the IDH1 gene at the Arg132 residue (R132) results in a gain-of-function mutant IDH1 (mut. IDH1) that reduces α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), consuming NADPH in the process. The inhibitors ivosidenib and olutasidenib potently bind mut. IDH1. Ivosidenib also inhibits w.t. IDH1 at an IC50 of 24–71 nM, whereas the IC50 of olutasidenib for w.t. IDH1 is 22,400 nM, indicating no inhibitory activity

Fig. 3

Influence of inhibitors on 2-HG levels in cells bearing IDH1 mutations [27]. (Adapted from Reinbold et al. [27].) LN18 cells were treated with the inhibitors ivosidenib, olutasidenib in DMSO (final concentrations: 5 μM). 2-HG levels were determined by anion-exchange chromatography couple to MS (n = 4 independent replicates). Control cells were generated by transduction with lentiviral vectors containing no IDH1. Box-and-whisker plots: The center line is the median and the bounds are 25th and 75th percentile values. The whiskers are the min and max measured 2-HG levels for each experimental group

Fig. 4

Binding of olutasidenib in single- or double-mutant IDH1. Left: Crystal structure of the binding pocket of single-mutant IDH1 R132H. Olutasidenib (blue) interacts with Asp279 in the IDH1 dimer interface. There is ample space remaining near the adjacent Ser280 site. Right: Generated image of the binding pocket of double-mutant IDH1 R132H/S280F based on the crystal structure of IDH1 R132H and grafting on the phenylalanine substitution. In the presence of a second site mutation whereby the serine is replaced with phenylalanine (S280F), the bulky benzene ring of phenylalanine increases steric hindrance and prevents larger molecules from interacting with Asp279 in the binding pocket. Due to its small size, olutasidenib is able to bind Asp279 even in the presence of the second site S280F mutation