6IO0

Human IDH1 R132C mutant complexed with compound A.

PDB DOI: https://doi.org/10.2210/pdb6IO0/pdb

Classification: OXIDOREDUCTASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2018-10-29 Released: 2019-10-30
Deposition Author(s): Suzuki, M., Baba, D., Hanzawa, H.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.20 ?
R-Value Free: 0.255
R-Value Work: 0.190
R-Value Observed: 0.193

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

A Potent Blood-Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model.

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.

(2020) Mol Cancer Ther 19: 375-383

PubMed: 31727689 Search on PubMed
DOI: https://doi.org/10.1158/1535-7163.MCT-18-1349
Primary Citation of Related Structures:
6IO0

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.

Organizational Affiliation

Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.

Macromolecule Content

Total Structure Weight: 97.01 kDa
Atom Count: 6,667
Modelled Residue Count: 800
Deposited Residue Count: 828
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Isocitrate dehydrogenase [NADP] cytoplasmic	A, B	414	Homo sapiens	Mutation(s): 1 Gene Names: IDH1, PICD EC: 1.1.1.42
UniProt & NIH Common Fund Data Resources
Find proteins for O75874 (Homo sapiens) Explore O75874 Go to UniProtKB: O75874
PHAROS: O75874 GTEx: ENSG00000138413
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O75874
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain O [auth B] MOL2 format, chain D [auth A] MOL2 format, chain O [auth B] mmCIF format, chain D [auth A] mmCIF format, chain O [auth B]	D [auth A], O [auth B]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain D [auth A] Focus chain O [auth B] Interactions & Density Focus chain D [auth A] Focus chain O [auth B]
AOU Query on AOU Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain N [auth B] MOL2 format, chain C [auth A] MOL2 format, chain N [auth B] mmCIF format, chain C [auth A] mmCIF format, chain N [auth B]	C [auth A], N [auth B]	(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 C₂₅ H₂₀ Cl₂ N₂ O₄ UIMYWZDHAJEOJS-ZHACJKMWSA-N		Interactions Focus chain C [auth A] Focus chain N [auth B] Interactions & Density Focus chain C [auth A] Focus chain N [auth B]
CIT Query on CIT Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain P [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain P [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain P [auth B]	E [auth A], F [auth A], P [auth B]	CITRIC ACID C₆ H₈ O₇ KRKNYBCHXYNGOX-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain P [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain P [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	G [auth A] H [auth A] I [auth B] J [auth B] K [auth B] G [auth A], H [auth A], I [auth B], J [auth B], K [auth B], L [auth B], M [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Focus chain L [auth B] Focus chain M [auth B]