AG-120 (Ivosidenib)

• CAT Number: I001475
• CAS Number: 1448346-63-1
• Molecular Formula: C28H22ClF3N6O3
• Molecular Weight: 582.968
• Purity: ≥95%
• Target: IDH1 inhibitor
• Solubility: Soluble in DMSO, not in water
• Storage: 0 - 4°Cfor short term (days to weeks), or -20 °C for long term (months).
• IUPAC Name: (2S)-N-[1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide
• InChI: InChI=1S/C28H22ClF3N6O3/c29-21-4-2-1-3-20(21)25(26(40)36-18-11-28(31,32)12-18)37(19-10-17(30)14-34-15-19)27(41)22-5-6-24(39)38(22)23-9-16(13-33)7-8-35-23/h1-4,7-10,14-15,18,22,25H,5-6,11-12H2,(H,36,40)/t22-,25?/m0/s1
• InChIKey: WIJZXSAJMHAVGX-XADRRFQNSA-N
• SMILES: C1CC(=O)N(C1C(=O)N(C2=CC(=CN=C2)F)C(C3=CC=CC=C3Cl)C(=O)NC4CC(C4)(F)F)C5=NC=CC(=C5)C#N

AG-120, also known as Ivosidenib (CAT: I001475), is an inhibitor of isocitrate dehydrogenase type 1 (IDH1) and exhibits potential as an antineoplastic agent. By specifically targeting the mutated form of IDH1 found in the cytoplasm, AG-120 inhibits the production of 2-hydroxyglutarate (2HG), an oncometabolite associated with tumor progression. This inhibition of 2HG formation may induce cellular differentiation and suppress cellular proliferation in tumor cells expressing mutant IDH1. AG-120 holds promise as a therapeutic option in the treatment of IDH1-mutated malignancies, such as acute myeloid leukemia (AML) and cholangiocarcinoma.

Reference

1:Clin Lymphoma Myeloma Leuk. 2016 Aug;16(8):460-5. doi: 10.1016/j.clml.2016.04.006. Epub 2016 May 5. Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.Birendra KC,DiNardo CD, PMID: 27245312 PMCID: PMC4983480 [Available on 2017-08-01] DOI: 10.1016/j.clml.2016.04.006 Abstract: BACKGROUND: Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described.PATIENTS AND METHODS: We describe 3 patients who developed clinically apparent DS during monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML.RESULTS: AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same time frame as clinical response, strengthening the purported mechanism of targeted mutant IDH inhibitor therapy via successful myeloid maturation. Symptoms of DS were nonspecific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis.CONCLUSION: DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients might present with nonspecific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids, and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.Copyright © 2016 Elsevier Inc. All rights reserved.