5.09880

IDH2 Inhibitor, R140Q Somatic Mutant-Specific, AGI-6780

• Synonym(s): IDH2 Inhibitor, R140Q Somatic Mutant-Specific, AGI-6780, Isocitrate Dehydrogenase 2 R140 Somatic Mutant Inhibitor, AGI6780
• Empirical Formula (Hill Notation): C₂₁H₁₈F₃N₃O₃S₂
• CAS Number: 1432660-47-3
• Molecular Weight: 481.51
• UNSPSC Code: 12352200
• NACRES: NA.77

Properties

• Assay: ≥95% (HPLC)
• Quality Level: 100
• form: powder
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: off-white
• solubility: DMSO: 100 mg/mL
• storage temp.: 2-8°C
• InChI: 1S/C21H18F3N3O3S2/c22-21(23,24)14-2-1-3-16(10-14)25-20(28)26-19-11-17(32(29,30)27-15-4-5-15)6-7-18(19)13-8-9-31-12-13/h1-3,6-12,15,27H,4-5H2,(H2,25,26,28)
• InChI key: CCAWRGNYALGPQH-UHFFFAOYSA-N

Description

General description

A cell-permeable urea sulfonamide that inhibits the activity of Isocitrate Dehydrogenase 2 (IDH2) R140Q mutant-containing dimers in an α-ketoglutarate/α-KG-non-competitive and NADPH-uncompetitive manner by stabilizing the mutant dimers in an inactive conformation via a high-affinity allosteric interaction at the dimer interface with a slow-binding kinetic (k_on = 5.8 x 10⁴/M/min; k_off = 8.3 x 10^-3/min), while displaying much reduced potency against wt IDH2 dimer-catalyzed α-KG production and little or no activity toward wt IDH1 or R132H IDH2 mutant. Selectively inhibits 2-HG production in IDH2 R140Q, but not R132H, mutant-expressing U87 cultures (IC₅₀ in 48 h = 11 nM vs. >100 µM). AGI-6780 treatment (5 µM) of primary bone marrow cultures from AML patients with R140Q mutation is shown to reactivate the differentiation of immature AML blasts without cytotoxicity.

A cell-permeable ureido-benzenesulfonamide that inhibits α-ketoglutarate (α-KG)-to-(R)-2-hydroxyglutarate (2-HG) conversion catalyzed by Isocitrate Dehydrogenase-2 (IDH2) R140Q mutant-containing dimers (IC₅₀/preincubation time = 4 nM/16 h & 120 nM/1 h against R140Q-wt heterodimer; 23 nM/16 h & 170 nM/1 h against R140Q homodimer) in a substrate-non-competitive and NADPH-uncompetitive manner by targeting the dimer interface via a high affinity allosteric interaction with a slow-binding kinetic (k_on = 5.8 x 10⁴/M/min; k_off = 8.3 x 10^-3/min) and stabilizing the mutant dimers in an inactive conformation, while displaying much reduced potency against wt IDH2 dimer-catalyzed α-KG production (IC₅₀/preincubation time = 190 nM/16 h & 2.7 µM/1 h) and little or no activity toward LDHA, 3PGDH, GDH, G6PDH, R132H mutant or wt IDH1. Selectively inhibits 2-HG production in R140Q IDH2-expressing U87 glioblastoma & TF-1 erythroleukemia, but not R132H-expressing U87 cultures (IC₅₀ in 48 h = 11 nM, 18 nM, and >100 µM, respectively) and sensitizes R140Q IDH2-expressing TF-1 to EPO-induced erythroid differentiation. Likewise, inhibition of 2-HG production in primary bone marrow cultures from AML patients with R140Q mutation (complete inhibition with 5 µM AGI-6780) is shown to reactivate the differentiation of immature AML blasts without cytotoxicity. IDH1 Inhibitor, R132 Somatic Mutant-Specific, AGI-5198 (>Cat. No. 410972) is also available.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
(IDH2) R140Q mutants

Reversible: yes

Target IC₅₀: 4 nM/16 h & 120 nM/1 h against R140Q-wt heterodimer

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Other Notes

Wang, F., et al. 2013. Science340, 622.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Safety Information

• Storage Class Code: 11 - Combustible Solids
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable