Enasidenib (AG-221)
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MedKoo CAT#: 206438

CAS#: 1446502-11-9 (free base)

Description: Enasidenib, also known as AG-221 and CC-90007, is a potent and selective IDH2 inhibitor with potential anticancer activity (IDH2 = Isocitrate dehydrogenase 2). The mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer . The inhibition of mutant IDH2 and its neoactivity is therefore a potential therapeutic treatment for cancer.

Chemical Structure

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Enasidenib (AG-221)
CAS# 1446502-11-9 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206438
Name: Enasidenib (AG-221)
CAS#: 1446502-11-9 (free base)
Chemical Formula: C19H17F6N7O
Exact Mass: 473.14
Molecular Weight: 473.380
Elemental Analysis: C, 48.21; H, 3.62; F, 24.08; N, 20.71; O, 3.38

Price and Availability

Size Price Availability Quantity
10mg USD 90 Ready to ship
25mg USD 150 Ready to ship
50mg USD 225 Ready to ship
100mg USD 350 Ready to ship
200mg USD 550 Ready to ship
500mg USD 1150 Ready to ship
1g USD 2150 Ready to ship
2g USD 4050 Ready to ship
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Related CAS #: 1650550-25-6 (mesylate)   1446502-11-9 (free base)  

Synonym: AG-221; AG 221; AG221; CC-90007; CC 90007; CC90007; Enasidenib; Idhifa

IUPAC/Chemical Name: 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol

InChi Key: DYLUUSLLRIQKOE-UHFFFAOYSA-N

InChi Code: InChI=1S/C19H17F6N7O/c1-17(2,33)9-27-15-30-14(11-4-3-5-12(29-11)18(20,21)22)31-16(32-15)28-10-6-7-26-13(8-10)19(23,24)25/h3-8,33H,9H2,1-2H3,(H2,26,27,28,30,31,32)

SMILES Code: CC(O)(C)CNC1=NC(C2=NC(C(F)(F)F)=CC=C2)=NC(NC3=CC(C(F)(F)F)=NC=C3)=N1

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: Enasidenib is an inhibitor of the IDH2 mutant enzymes with IC50s of 100 and 400 nM against IDH2R140Q and IDH2R172K, respectively.
In vitro activity: The inhibitory effects of enasidenib and its metabolite AGI-16903 on recombinant human nucleoside transporters (hNTs) in hNT-producing Xenopus laevis oocytes, and azacitidine uptake in a normal B-lymphoblast peripheral blood cell line (PBC) and acute myeloid leukemia (AML) cell lines were investigated. Enasidenib inhibited hENT1, hENT2, hENT3, and hENT4 in oocytes with IC50 values of 7, 63, 27, and 76 μM, respectively, but exhibited little inhibition of hCNT1-3. Azacitidine uptake was more than 2-fold higher in AML cells than in PBC. Enasidenib inhibited azacitidine uptake into OCI-AML2, TF-1 and PBC cells in a concentration-dependent manner with IC50 values of 0.27, 1.7, and 1.0 µM in sodium-containing transport medium, respectively. IC50 values shifted approximately 100-fold higher when human plasma was used as the incubation medium (27 µM in OCI-AML2, 162 µM in TF-1, and 129 µM in PBC), likely due to high human plasma protein binding of enasidenib (98.5% bound). Reference: Xenobiotica. 2019 Oct;49(10):1229-1236. https://www.tandfonline.com/doi/abs/10.1080/00498254.2018.1539783?journalCode=ixen20
In vivo activity: To determine if the in vivo differentiation effects of AG-221 were associated with a survival benefit, an aggressive human xenograft mouse model was established using early passage cells from a patient with AML harboring IDH2R140Q (AML-4; Supplementary Table S3). AG-221 treatment was well tolerated and, compared with vehicle, conferred a dose-dependent survival advantage that was statistically significant at doses of 15 and 45 mg/kg; there was also a statistically significant survival advantage with AG-221 45 mg/kg versus the vehicle (P < 0.0001; Fig. 4B). Four animals in the AG-221 45 mg/kg group remained on treatment after day 84, and all survived until study termination (day 130). This survival advantage was accompanied by reductions in 2HG levels and cell differentiation. As measured 8 hours after last dose (day 84), AG-221 exhibited a linear pharmacokinetic profile and effective inhibition of 2HG production in blood (89.7%, 91.9%, and 93.6%) and spleen (97.8%, 99.8, and 99.9%) at doses of 5, 15, and 45 mg/kg b.i.d., respectively. In BM, 2HG levels were below the limit of quantitation in all AG-221–treated animals except for two in the lowest dose group (both 93.3% inhibition; Supplementary Table S6). Reference: Cancer Discov. 2017 May;7(5):478-493. https://cancerdiscovery.aacrjournals.org/content/7/5/478.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 91.7 193.65
Ethanol 100.0 211.25

Preparing Stock Solutions

The following data is based on the product molecular weight 473.38 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Tong Z, Yerramilli U, Yao S, Young JD, Hoffmann M, Surapaneni S. In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903. Xenobiotica. 2019 Oct;49(10):1229-1236. doi: 10.1080/00498254.2018.1539783. Epub 2018 Nov 29. PMID: 30394160. 2. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13. PMID: 28193778.
In vitro protocol: 1. Tong Z, Yerramilli U, Yao S, Young JD, Hoffmann M, Surapaneni S. In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903. Xenobiotica. 2019 Oct;49(10):1229-1236. doi: 10.1080/00498254.2018.1539783. Epub 2018 Nov 29. PMID: 30394160.
In vivo protocol: 1. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, Choe S, Jin L, Konteatis Z, Cianchetta G, Saunders JO, Salituro FG, Quivoron C, Opolon P, Bawa O, Saada V, Paci A, Broutin S, Bernard OA, de Botton S, Marteyn BS, Pilichowska M, Xu Y, Fang C, Jiang F, Wei W, Jin S, Silverman L, Liu W, Yang H, Dang L, Dorsch M, Penard-Lacronique V, Biller SA, Su SM. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13. PMID: 28193778.

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1: Dittakavi S, Hallur G, Purra BR, Kiran V, Zakkula A, Mullangi R. Validated LC-MS/MS Method for Simultaneous Quantitation of Enasidenib and its Active Metabolite, AGI-16903 in Small Volume Mice Plasma: Application to a Pharmacokinetic Study. Drug Res (Stuttg). 2019 Oct 25. doi: 10.1055/a-1024-3623. [Epub ahead of print] PubMed PMID: 31652462.

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3: Reed DR, Elsarrag RZ, Morris AL, Keng MK. Enasidenib in acute myeloid leukemia: clinical development and perspectives on treatment. Cancer Manag Res. 2019 Aug 30;11:8073-8080. doi: 10.2147/CMAR.S162784. eCollection 2019. PubMed PMID: 31564968; PubMed Central PMCID: PMC6724422.

4: Del Principe MI, Paterno G, Palmieri R, Maurillo L, Buccisano F, Venditti A. An evaluation of enasidenib for the treatment of acute myeloid leukemia. Expert Opin Pharmacother. 2019 Nov;20(16):1935-1942. doi: 10.1080/14656566.2019.1654456. Epub 2019 Aug 27. PubMed PMID: 31454277.

5: Zakkula A, Dittakavi S, Maniyar MM, Syed N, Sulochana SP, Zainuddin M, Mullangi R. Validated HPLC method for simultaneous quantification of mutant IDH1/2 inhibitors (enasidenib, ivosidenib and vorasidenib) in mouse plasma: Application to a pharmacokinetic study. Biomed Chromatogr. 2019 Nov;33(11):e4658. doi: 10.1002/bmc.4658. Epub 2019 Sep 2. PubMed PMID: 31325170.

6: Galkin M, Jonas BA. Enasidenib in the treatment of relapsed/refractory acute myeloid leukemia: an evidence-based review of its place in therapy. Core Evid. 2019 Apr 26;14:3-17. doi: 10.2147/CE.S172912. eCollection 2019. PubMed PMID: 31118877; PubMed Central PMCID: PMC6503332.

7: Pollyea DA, Tallman MS, de Botton S, Kantarjian HM, Collins R, Stein AS, Frattini MG, Xu Q, Tosolini A, See WL, MacBeth KJ, Agresta SV, Attar EC, DiNardo CD, Stein EM. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019 Nov;33(11):2575-2584. doi: 10.1038/s41375-019-0472-2. Epub 2019 Apr 9. PubMed PMID: 30967620.

8: Li Y, Connarn JN, Chen J, Tong Z, Palmisano M, Zhou S. Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment. Clin Pharmacol. 2019 Feb 15;11:39-50. doi: 10.2147/CPAA.S192687. eCollection 2019. PubMed PMID: 30858735; PubMed Central PMCID: PMC6385784.

9: Myers RA, Wirth S, Williams S, Kiel PJ. Enasidenib: An Oral IDH2 Inhibitor for the Treatment of Acute Myeloid Leukemia. J Adv Pract Oncol. 2018 May-Jun;9(4):435-440. Epub 2018 May 1. Review. PubMed PMID: 30719396; PubMed Central PMCID: PMC6347084.

10: Dittakavi S, Jat RK, Mullangi R. Quantitative analysis of enasidenib in dried blood spots of mouse blood using an increased-sensitivity LC-MS/MS method: Application to a pharmacokinetic study. Biomed Chromatogr. 2019 Jun;33(6):e4491. doi: 10.1002/bmc.4491. Epub 2019 Feb 7. PubMed PMID: 30663096.

11: Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019 Feb 14;133(7):676-687. doi: 10.1182/blood-2018-08-869008. Epub 2018 Dec 3. PubMed PMID: 30510081; PubMed Central PMCID: PMC6384189.

12: Tong Z, Yerramilli U, Yao S, Young JD, Hoffmann M, Surapaneni S. In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903. Xenobiotica. 2019 Oct;49(10):1229-1236. doi: 10.1080/00498254.2018.1539783. Epub 2018 Nov 29. PubMed PMID: 30394160.

13: Li Y, Liu L, Gomez D, Chen J, Tong Z, Palmisano M, Zhou S. Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects. Pharmacol Res Perspect. 2018 Oct 23;6(6):e00436. doi: 10.1002/prp2.436. eCollection 2018 Dec. PubMed PMID: 30386625; PubMed Central PMCID: PMC6199364.

14: Dogra R, Bhatia R, Shankar R, Bansal P, Rawal RK. Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia. Anticancer Agents Med Chem. 2018;18(14):1936-1951. doi: 10.2174/1871520618666181025091128. Review. PubMed PMID: 30360730.

15: Galeotti J, Coombs CC. Enasidenib-induced eosinophilic differentiation in a patient with acute myeloid leukaemia with IDH2 and U2AF1 mutations. Br J Haematol. 2019 Feb;184(4):496. doi: 10.1111/bjh.15609. Epub 2018 Oct 18. PubMed PMID: 30334576.

16: Krämer A, Bochtler T. Enasidenib. Recent Results Cancer Res. 2018;212:187-197. doi: 10.1007/978-3-319-91439-8_9. PubMed PMID: 30069631.

17: Abou Dalle I, DiNardo CD. The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia. Ther Adv Hematol. 2018 Jul;9(7):163-173. doi: 10.1177/2040620718777467. Epub 2018 Jun 1. Review. PubMed PMID: 30013764; PubMed Central PMCID: PMC6041864.

18: Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Alsafadi S, Vijayabaskar MS, Peniket A, Bernard OA, Agresta S, Yen K, MacBeth K, Stein E, Vassiliou GS, Levine R, De Botton S, Thakurta A, Penard-Lacronique V, Vyas P. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med. 2018 Aug;24(8):1167-1177. doi: 10.1038/s41591-018-0115-6. Epub 2018 Jul 16. PubMed PMID: 30013198.

19: Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Available from http://www.ncbi.nlm.nih.gov/books/NBK500925/ PubMed PMID: 29999984.

20: Roboz GJ. Enasidenib for relapsed/refractory acute myeloid leukemia with IDH2 mutations: optimizing the patient experience. Clin Adv Hematol Oncol. 2018 May;16(5):322-325. PubMed PMID: 29851927.