6IO0

Human IDH1 R132C mutant complexed with compound A.

Summary for 6IO0

• Entry DOI: 10.2210/pdb6io0/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, (2E)-3-{3-[3-(2,6-dichlorophenyl)-5-(propan-2-yl)-1,2-oxazole-4-carbonyl]-1-methyl-1H-indol-7-yl}prop-2-enoic acid, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: iso-citrate dehydrogenase, allosteric inhibitor, nadph, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 97010.90

Authors

Suzuki, M.,Baba, D.,Hanzawa, H. (deposition date: 2018-10-29, release date: 2019-10-30, Last modification date: 2024-03-27)

Primary citation

Machida, Y.,Nakagawa, M.,Matsunaga, H.,Yamaguchi, M.,Ogawara, Y.,Shima, Y.,Yamagata, K.,Katsumoto, T.,Hattori, A.,Itoh, M.,Seki, T.,Nishiya, Y.,Nakamura, K.,Suzuki, K.,Imaoka, T.,Baba, D.,Suzuki, M.,Sampetrean, O.,Saya, H.,Ichimura, K.,Kitabayashi, I.
A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.
Mol.Cancer Ther., 19:375-383, 2020

PubMed Abstract: Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood-brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.

PubMed: 31727689
DOI: 10.1158/1535-7163.MCT-18-1349

Experimental method

X-RAY DIFFRACTION (2.2 Å)