Discovery and Optimization of 2H-1λ²-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer

Abstract

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5­(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

Diminishing GSH-Adduct Formation of Tricyclic Diazepine-based Mutant IDH1 Inhibitors

“…Inhibiting mutant IDH1 has been clinically validated, with ivosidenib (AG-120) approved by the FDA for the treatment of relapsed/refractory AML . A handful of other small molecule mutant IDH1 inhibitors, including IDH1/2 dual-inhibitor AG-881, BAY-1436032, GSK321, IDH305, FT-2102, and others, , have also shown efficacy in various preclinical and clinical studies, potentially offering new treatment options for different tumor types carrying IDH1 mutations.…”

Applications of Isosteres of Piperazine in the Design of Biologically Active Compounds: Part 2

“…Replacement of the terminal piperazine element of the mutant isocitrate dehydrogenase 1 (IDH1) inhibitor 213 with 2,6-diazaspiro[3.3]­heptane in compound 214 was an effective molecular edit that preserved enzyme inhibitory potency, although in this example, there was no significant improvement in developability properties …”

“…Over 14 days of drug administration at doses of 200−600 mg/day, the mean reduction in RBC 2,3-DPG levels was claimed to be 56% along, with a 68% increase in ATP concentrations. Interestingly, FT709 (115), an analogue of compound 114, has recently been characterized as a potent and selective inhibitor of the catalytic acitvity of the deubiquitylase (DUB) enzyme USP9X, with an IC 50 value of 82 nM, in a biochemical assay. 51 The hexahydropyrrolo [3,4-c]pyrrole heterocycle 9 has also found application as a replacement for piperazine and other heterocycle-based scaffolds in the design of inhibitors of autotaxin (ATX), a lysophospholipase D enzyme that converts lysophosphatidylcholine into lysophosphatidic acid (LPA).…”

“…114 Replacement of the terminal piperazine element of the mutant isocitrate dehydrogenase 1 (IDH1) inhibitor 213 with 2,6-diazaspiro- [3.3]heptane in compound 214 was an effective molecular edit that preserved enzyme inhibitory potency, although in this example, there was no significant improvement in developability properties. 115 In those circumstances, where a piperazine heterocycle functions as a scaffold, the demands for topographical mimicry on the application of a bioisostere can be heightened. This is exemplified in the study of the dopamine ligands 216−220 that were designed to explore the effect of substituting the piperazine heterocycle of compound 215 in search of selective D 3 receptor antagonists (Figure 20).…”

Recent advances of IDH1 mutant inhibitor in cancer therapy

“…Jason M. et al reported a class of mIDH1 inhibitors with 2H-1λ2-Pyridin-2-one backbone ( Rohde et al, 2021 ). The most potent compound 14 ( Figure 8B ) inhibits IDH1 R132H/R132C with IC 50 values of 81 and 72 nM, respectively.…”