In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site

Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) are found in 6% of AML patients. Mutant IDH produces R-2-hydroxyglutarate (R2HG), which induces histone-and DNA-hypermethylation through inhibition of epigenetic regulators, thus linking metabolism to tumorigenesis. Here we report the biochemical characterization, in vivo antileukemic effects, structural binding and molecular mechanism of the inhibitor HMS-101, which inhibits the enzymatic activity of mutant IDH1 (IDH1mut). Treatment of IDH1mut primary AML cells reduced 2-hydroxyglutarate levels (2HG) and induced myeloid differentiation in vitro. Co-crystallization of HMS-101 and mutant IDH1 revealed that HMS-101 binds to the active site of IDH1mut in close proximity to the regulatory segment of the enzyme in contrast to other IDH1 inhibitors. HMS-101 also suppressed 2HG production, induced cellular differentiation and prolonged survival in a syngeneic mutant IDH1 mouse model and a patient-derived human AML xenograft model in vivo. Cells treated with Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction—a retrospective propensity score analysis

“…Thus, careful baseline assessment of cardiovascular risk factors and genetic risk factors including the IDH mutation status as well as baseline measurement of cardiac function by a cardio-oncology specialist team should be performed in these AML patients (especially when adjuvant anthracyclines are used). It will be interesting whether IDH inhibitors, that effectively reduce R-2HG levels in vivo, can reduce the cardiovascular risk observed in our study [42][43][44][45][46].…”

“…It will be interesting whether IDH inhibitors, that effectively reduce R-2HG levels in vivo, can reduce the cardiovascular risk observed in our study. 42 – 46 …”

Isocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias

“…A recent study reported the characterization of HMS-101 a new IDH1 inhibitor with the peculiar property to interact with the active site of IDH1 -mutant in close proximity to the regulatory segment of the enzyme [ 175 ]. The inhibitor exerted a potent anti-leukemic effect on mutant IDH1 leukemia models; interestingly, leukemic cells treated with this inhibitor showed a marked upregulation of the transcription factors CEBPA and PU.1 and a decrease of cyclin A2 [ 175 ].…”

Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results

“…BAY1436032 is an oral small-molecule inhibitor of mIDH1 that is active in preclinical models of mIDH1 cancer [ 15 – 17 ]. Most mIDH1 inhibitors, including BAY1436032, reportedly interact with an allosteric site on the mutant enzyme, although an inhibitor which interacts directly with the active site was recently described [ 18 ]. Preclinical experiments focusing on mIDH1 AML found that BAY1436032 inhibits R-2HG production and colony growth in vitro , while promoting leukemic blast clearance, myeloid differentiation, and survival in animal models [ 16 ].…”