Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening

Duan, Zhe; Liu, Ying; Niu, Liping; Wang, Jun; Feng, Mingqian; Chen, Hua; Luo, Cheng

doi:10.1016/j.bmc.2019.05.040

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…The screening was performed against ZINC Drug database with 2924 molecules. Duan et al employed structure-activity relationship based study along with MD simulation to discover DC_H31 as novel mIDH1 inhibitor [20]. Recently, Wang et al combined in-silico and in-vitro methods and reported 10 molecules with signi cant experimental activity against mIDH1 [21].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Murali

Ramanathan

2022

J. Comput. Biophys. Chem.

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Neomorphic transformations in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors showed modest brain penetrating potential and dose-limiting toxicity. Herein, we elucidate virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, a structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified Abemaciclib as the hit against mIDH1. Notably, abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamics simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100[Formula: see text]ns. It is worth noting that benzimidazole moiety of abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that abemaciclib has the potential as a lead molecule against glioma. Indeed, the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.

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Section: Introductionmentioning

confidence: 99%

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Murali

Ramanathan

2022

J. Comput. Biophys. Chem.

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“…Recently, a new small molecular allosteric inhibitor of IDH1 R132H/C, called DC_H31, has been developed. It could reduce the 2-HG level and inhibit cell proliferation and promote cell differentiation in HT1080 cell lines [72], However, in vivo trials are needed to validate these effects to develop this drug as a promising new targeted inhibitor shortly.…”

Section: Introductionmentioning

confidence: 99%

Isocitrate dehydrogenase inhibitors in acute myeloid leukemia

Liu

Gong

2019

Biomark Res

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Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.

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“…In addition, this new virtual screening strategy should be further optimized to introduce more novel scaffold mIDH1 inhibitors. DC_H31 is a new type of IDH1 R132H/C inhibitor, which acts through an allosteric mechanism 181 . At the cellular level, DC_H31 can inhibit cell proliferation in HT-1080 cells, promote cell differentiation, and reduce the production of D-2HG 181 .…”

Section: Idh1 Inhibitorsmentioning

confidence: 99%

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Liu

et al. 2023

Acta Pharmaceutica Sinica B

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Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening

Cited by 12 publications

References 28 publications

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Identification of Novel Mutant (R132H) Isocitrate Dehydrogenase 1 Inhibitors for Glioma Therapy

Isocitrate dehydrogenase inhibitors in acute myeloid leukemia

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

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