vorasidenib   Click here for help

GtoPdb Ligand ID: 10663

Synonyms: AG-881 | AG881
PDB Ligand
Compound class: Synthetic organic
Comment: Vorasidenib (AG-881) inhibits mutant forms of the isocitrate dehydrogenases (IDH1 and IDH2) [3] that catalyse the generation of the oncogenic metabolite d-2-hydroxyglutarate (2-HG). This compound and others, and their use for treating cancer are claimed in patent US10028961 [4]. Vorasidenib can cross the blood brain barrier, and is being proposed as a chemotherapeutic for IDH mutation +ve cancers including gliomas [2,8] and hematological malignancies [1]. X-ray cocrystal structures of vorasidenib with mutant IDH1 and mutant IDH2 have been deposited with the RCSB Protein Data Bank [3,5]. The X-ray structures show that vorasidenib binds at an allosteric pocket formed in IDH homodimers, at the interface of the two monomers.
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 7
Topological polar surface area 75.62
Molecular weight 414.08
XLogP 4.99
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES Clc1cccc(n1)c1nc(nc(n1)N[C@@H](C(F)(F)F)C)N[C@@H](C(F)(F)F)C
Isomeric SMILES Clc1cccc(n1)c1nc(nc(n1)N[C@@H](C(F)(F)F)C)N[C@@H](C(F)(F)F)C
InChI InChI=1S/C14H13ClF6N6/c1-6(13(16,17)18)22-11-25-10(8-4-3-5-9(15)24-8)26-12(27-11)23-7(2)14(19,20)21/h3-7H,1-2H3,(H2,22,23,25,26,27)/t6-,7-/m1/s1
InChI Key QCZAWDGAVJMPTA-RNFRBKRXSA-N
References
1. Boddu P, Borthakur G. (2017)
Therapeutic targeting of isocitrate dehydrogenase mutant AML.
Expert Opin Investig Drugs, 26 (5): 525-530. [PMID:28388242]
2. Karpel-Massler G, Nguyen TTT, Shang E, Siegelin MD. (2019)
Novel IDH1-Targeted Glioma Therapies.
CNS Drugs, 33 (12): 1155-1166. [PMID:31768950]
3. Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, Chen Y, Narayaraswamy R, Tong S, Wang F et al.. (2020)
Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma.
ACS Med Chem Lett, 11 (2): 101-107. DOI: 10.1021/acsmedchemlett.9b00509 [PMID:32071674]
4. Konteatis Zd, Popovici-Muller J, Travins JM, Zahler R, Cai Z, Zhou D. (2018)
Therapeutically active compounds and their methods of use.
Patent number: US10028961B1. Assignee: Agios Pharmaceuticals. Priority date: 11/07/2013. Publication date: 24/07/2018.
5. Ma R, Yun CH. (2018)
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2.
Biochem Biophys Res Commun, 503 (4): 2912-2917. [PMID:30131249]
6. Mellinghoff IK, Penas-Prado M, Peters KB, Burris 3rd HA, Maher EA, Janku F, Cote GM, de la Fuente MI, Clarke JL, Ellingson BM et al.. (2021)
Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial.
Clin Cancer Res, 27 (16): 4491-4499. [PMID:34078652]
7. Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, Mendez J, Yust-Katz S, Welsh L, Mason WP et al.. (2023)
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.
N Engl J Med, 389 (7): 589-601. [PMID:37272516]
8. Sharma N, Mallela AN, Shi DD, Tang LW, Abou-Al-Shaar H, Gersey ZC, Zhang X, McBrayer SK, Abdullah KG. (2023)
Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials.
Neurooncol Adv, 5 (1): vdad053. [PMID:37287696]