[CAS NO. 1446502-11-9] Enasidenib
PRODUCTS SPECIFICATIONS [1446502-11-9]
DESCRIPTION [1446502-11-9]
Overview
| MDL | MFCD29472245 |
|---|---|
| Molecular Weight | 473.38 |
| Molecular Formula | C19H17F6N7O |
| SMILES | CC(O)(C)CNC1=NC(C2=NC(C(F)(F)F)=CC=C2)=NC(NC3=CC(C(F)(F)F)=NC=C3)=N1 |
8 Publications Citing Use of MCE
- [1]Sci Adv. 2022 Sep 30;8(39):eabq5575.
- [2]Nat Commun. 2022 Aug 15;13(1):4785.
- [3]Cell Rep. 2022 Feb 15;38(7):110391.
- [4]Sci Rep. 2018 Jun 21;8(1):9472.
- [5]Sci Rep. 2017 Oct 6;7(1):12758.
- [6]ACS Med Chem Lett. 2018 May 1;9(7):606-611.
- [7]Spectrochim Acta A Mol Biomol Spectrosc. 22 December 2021, 120790.
- [8]Univerzita Karlova v Praz. 2021 Jul.
Summary
Enasidenib is an oral, potent, reversible, selective inhibitor of the IDH2 mutant enzymes, with IC 50 s of 100 and 400 nM against IDH2 R140Q and IDH2 R172K , respectively.
IC50 & Target
IC50: 100 nM (IDH2 R140Q ), 400 nM (IDH2 R172K ) [1]
In Vitro
Enasidenib (AG-221) reverses the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells. Enasidenib induces differentiation and impairs self-renewal of IDH2-mutant leukemia cells, effects that are further enhanced by simultaneous inhibition of Flt3 ITD . Enasidenib (AG-221) therapy induces differentiation of leukemic cells, with an increase in the CD11b + population and a decrease in the c-Kit + population in the peripheral blood at 2wks [2] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
Treatment with Enasidenib (AG-221) significantly improves survival in an IDH2-mutant acute myeloid leukemia (AML) primary xenograft mouse model [1] . Enasidenib (AG-221), a mutant IDH2 inhibitor, remodels the epigenetic state of IDH2-mutant cells and induces alterations in self-renewal/differentiation in IDH2-mutant AML model in vivo. Enasidenib treatment (10mg/kg or 100mg/kg bid) leads to a reduction in 2-HG in vivo (96.7% below pre-treatment levels). Moreover, Enasidenib treatment restores megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression (mean MEP% mean, 39% Veh vs 50% AG-221). Enasidenib therapy reverses the effects of mutant IDH2; a significant reduction is observed in DNA methylation, including 180 genes that have 20 or more hypomethylated differentially methylated cytosines (DMCs) following treatment. Enasidenib (100mg/kg bid) treatment of mice engrafted with Mx1-Cre IDH2 R140Q Flt3 ITD AML cells markedly reduces 2-hydroxyglutarate (2-HG) levels consistent with on target inhibition. Enasidenib inhibits mutant IDH2-mediated 2-HG production [2] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT03290443 | Celgene |
Hepatic Impairment
|
September 21, 2017 | Phase 1 |
| NCT03825796 | Jonsson Comprehensive Cancer Center|Jazz Pharmaceuticals |
Recurrent Acute Myeloid Leukemia
|
April 12, 2019 | Phase 2 |
| NCT04281498 | John Mascarenhas|Celgene Corporation|Incyte Corporation|Myeloproliferative Neoplasms Research Consortium|National Institutes of Health (NIH)|National Cancer Institute (NCI)|Icahn School of Medicine at Mount Sinai |
Accelerated+Blast-phase Myeloproliferative Neoplasm|Chronic-phase Myelofibrosis|IDH2 Mutation
|
January 20, 2021 | Phase 2 |
| NCT02443168 | Celgene |
Healthy Volunteers
|
May 14, 2015 | Phase 1 |
| NCT04522895 | Heinrich-Heine University, Duesseldorf|Celgene Corporation|Koordinierungszentrum für Klinische Studien Düsseldorf |
Leukemia, Myeloid, Acute|Myelodysplastic Syndromes|Chronic Myelomonocytic Leukemia|IDH2 Gene Mutation|IDH2 R172|IDH2 R140
|
August 27, 2020 | Phase 2 |
| NCT04774393 | M.D. Anderson Cancer Center |
Acute Myeloid Leukemia|Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
May 24, 2021 | Phase 1|Phase 2 |
| NCT04573582 | Celgene |
Hepatic Impairment
|
November 13, 2020 | Phase 1 |
| NCT04092179 | University Health Network, Toronto|Celgene|AbbVie |
Acute Myeloid Leukemia|Relapsed Cancer|Refractory Cancer|IDH2 Gene Mutation
|
November 5, 2020 | Phase 1|Phase 2 |
| NCT02632708 | Institut de Recherches Internationales Servier|Celgene Corporation|Servier |
Newly Diagnosed Acute Myeloid Leukemia (AML)|Untreated AML|AML Arising From Myelodysplastic Syndrome (MDS)|AML Arising From Antecedent Hematologic Disorder (AHD)|AML Arising After Exposure to Genotoxic Injury
|
December 31, 2015 | Phase 1 |
| NCT04955938 | University of Chicago |
IDH Mutation|IDH1 Mutation|IDH2 Gene Mutation|Blood Cancer|Myeloproliferative Neoplasm
|
October 29, 2021 | Phase 1 |
| NCT02218346 | Agios Pharmaceuticals, Inc.|Celgene Corporation |
Healthy Volunteers
|
August 2014 | Phase 1 |
| NCT05282459 | Tian Yi Zhang|Celgene Corporation|Stanford University |
Leukemia|Leukemia, Myeloid|Monocytic Leukemia
|
January 12, 2022 | Phase 1|Phase 2 |
| NCT03683433 | M.D. Anderson Cancer Center|National Cancer Institute (NCI) |
Acute Bilineal Leukemia|Acute Biphenotypic Leukemia|Chronic Myelomonocytic Leukemia|IDH2 Gene Mutation|Myelodysplastic Syndrome|Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
September 18, 2018 | Phase 2 |
| NCT03383575 | M.D. Anderson Cancer Center|National Cancer Institute (NCI)|Celgene |
Acute Myeloid Leukemia|Blasts 20-30 Percent of Bone Marrow Nucleated Cells|Chronic Myelomonocytic Leukemia|IDH2 Gene Mutation|Myelodysplastic Syndrome With Excess Blasts|Recurrent High Risk Myelodysplastic Syndrome|Refractory High Risk Myelodysplastic Syndrome
|
January 17, 2018 | Phase 2 |
| NCT05401097 | Alice Mims|Ohio State University Comprehensive Cancer Center |
Acute Myeloid Leukemia
|
August 1, 2022 | Phase 2 |
| NCT04310527 | Celgene |
Healthy Volunteers
|
October 9, 2019 | Phase 1 |
| NCT02813135 | Gustave Roussy, Cancer Campus, Grand Paris|National Cancer Institute, France |
Children, Adolescents and Young Adults With Refractory or Recurrent Malignancies
|
August 3, 2016 | Phase 1|Phase 2 |
| NCT02387866 | Celgene |
Healthy
|
March 2, 2015 | Phase 1 |
| NCT02677922 | Celgene |
Leukemia, Myeloid, Acute
|
June 3, 2016 | Phase 1|Phase 2 |
| NCT03744390 | Groupe Francophone des Myelodysplasies |
Myelodysplastic Syndromes|Leukemia Acute Myeloid
|
April 2, 2019 | Phase 2 |
| NCT03839771 | Stichting Hemato-Oncologie voor Volwassenen Nederland|Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG) |
Acute Myeloid Leukemia|Myelodysplastic Syndrome With Excess Blasts-2
|
March 1, 2019 | Phase 3 |
| NCT03728335 | City of Hope Medical Center|National Cancer Institute (NCI) |
Acute Myeloid Leukemia
|
July 11, 2019 | Phase 1 |
| NCT02577406 | Celgene |
Leukemia, Myeloid|Isocitrate Dehydrogenase
|
December 30, 2015 | Phase 3 |
| NCT03515512 | Massachusetts General Hospital|Celgene |
Acute Myeloid Leukemia|Chronic Myelomonocytic Leukemia
|
July 17, 2018 | Phase 1 |
| NCT04655391 | City of Hope Medical Center|National Cancer Institute (NCI) |
Recurrent Acute Myeloid Leukemia
|
June 25, 2022 | Phase 1 |
| NCT05010772 | M.D. Anderson Cancer Center|National Cancer Institute (NCI) |
Acute Myeloid Leukemia
|
October 25, 2021 | Phase 1 |
| NCT04203316 | Children´s Oncology Group|National Cancer Institute (NCI) |
Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
March 30, 2020 | Phase 2 |
| NCT02273739 | Celgene|Celgene Corporation |
Solid Tumor|Glioma|Angioimmunoblastic T-cell Lymphoma|Intrahepatic Cholangiocarcinoma|Chondrosarcoma
|
December 8, 2014 | Phase 1|Phase 2 |
| NCT03720366 | Celgene |
Leukemia, Myeloid, Acute
|
December 11, 2018 | Phase 1 |
| NCT03013998 | Beat AML, LLC |
Previously Untreated Acute Myeloid Leukemia
|
November 2016 | Phase 1|Phase 2 |
| NCT05441514 | City of Hope Medical Center|National Cancer Institute (NCI) |
Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
November 28, 2022 | Phase 1 |
| NCT01915498 | Celgene|Agios Pharmaceuticals, Inc. |
Hematologic Neoplasms
|
August 27, 2013 | Phase 1|Phase 2 |
| NCT03723057 | Celgene |
Acute Myeloid Leukemia
|
||
| NCT04075747 | Jazz Pharmaceuticals |
Acute Myeloid Leukemia
|
December 2, 2019 | Phase 1 |
| NCT03878524 | OHSU Knight Cancer Institute|Oregon Health and Science University |
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive|Anatomic Stage IV Breast Cancer AJCC v8|Anemia|Ann Arbor Stage III Hodgkin Lymphoma|Ann Arbor Stage III Non-Hodgkin Lymphoma|Ann Arbor Stage IV Hodgkin Lymphoma|Ann Arbor Stage IV Non-Hodgkin Lymphoma|Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative|Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive|Castration-Resistant Prostate Carcinoma|Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive|Hematopoietic and Lymphoid System Neoplasm|Locally Advanced Pancreatic Adenocarcinoma|Metastatic Breast Carcinoma|Metastatic Malignant Solid Neoplasm|Metastatic Pancreatic Adenocarcinoma|Myelodysplastic+Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis|Myelodysplastic+Myeloproliferative Neoplasm, Unclassifiable|Primary Myelofibrosis|Recurrent Acute Lymphoblastic Leukemia|Recurrent Acute Myeloid Leukemia|Recurrent Chronic Lymphocytic Leukemia|Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive|Recurrent Hematologic Malignancy|Recurrent Hodgkin Lymphoma|Recurrent Myelodysplastic Syndrome|Recurrent Myelodysplastic+Myeloproliferative Neoplasm|Recurrent Myeloproliferative Neoplasm|Recurrent Non-Hodgkin Lymphoma|Recurrent Plasma Cell Myeloma|Recurrent Small Lymphocytic Lymphoma|Refractory Acute Lymphoblastic Leukemia|Refractory Acute Myeloid Leukemia|Refractory Chronic Lymphocytic Leukemia|Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive|Refractory Chronic Myelomonocytic Leukemia|Refractory Hematologic Malignancy|Refractory Hodgkin Lymphoma|Refractory Malignant Solid Neoplasm|Refractory Myelodysplastic Syndrome|Refractory Myelodysplastic+Myeloproliferative Neoplasm|Refractory Non-Hodgkin Lymphoma|Refractory Plasma Cell Myeloma|Refractory Primary Myelofibrosis|Refractory Small Lymphocytic Lymphoma|Stage II Pancreatic Cancer AJCC v8|Stage III Pancreatic Cancer AJCC v8|Stage IV Pancreatic Cancer AJCC v8|Stage IV Prostate Cancer AJCC v8|Unresectable Pancreatic Adenocarcinoma
|
April 1, 2020 | Phase 1 |
| NCT05102370 | Memorial Sloan Kettering Cancer Center |
Clonal Cytopenia of Undetermined Significance|CCUS Clonal Cytopenia of Undetermined Significance
|
October 6, 2021 | Phase 1 |
| NCT03881735 | Roswell Park Cancer Institute|Celgene |
Blasts Under 5 Percent of Peripheral Blood White Cells|Bone Marrow Blasts Decreased by 50 Percent or More Compared to Pretreatment Level|IDH2 Gene Mutation|Recurrent Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia
|
December 2, 2019 | Phase 2 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : 50 mg/mL ( 105.62 mM ; Need ultrasonic)
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.1125 mL | 10.5623 mL | 21.1247 mL |
| 5 mM | 0.4225 mL | 2.1125 mL | 4.2249 mL |
| 10 mM | 0.2112 mL | 1.0562 mL | 2.1125 mL |
References
- [1] Exploring the Pathway: IDH Mutations and Metabolic Dysregulation in Cancer Cells: A Novel Therapeutic Target. MAY 29, 2015
- [2] Alan H. Shih, et al. AG-221, a Small Molecule Mutant IDH2 Inhibitor, Remodels the Epigenetic State of IDH2-Mutant Cells and Induces Alterations in Self-Renewal/Differentiation in IDH2-Mutant AML Model in Vivo. Blood 2014 124:437.