Enasidenib

Summary

Enasidenib (CHEMBL3989908) is an approved small-molecule antineoplastic agent (ATC L01XM01) targeting IDH2; indicated across 8 conditions including leukemia and myelodysplastic syndrome; with CIViC clinical evidence for 2 variant-indication associations (e.g. IDH2 Mutation in acute myeloid leukemia).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L01XM01
• Targets: 1 (IDH2)
• Indications: 8 conditions
• Clinical trials: 43
• Precision-oncology evidence (CIViC): 2 variant–indication associations
• Chemistry: 473.4 Da · C19H17F6N7O

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL3989908
Name	Enasidenib
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	89683805
ChEBI	CHEBI:145374
ATC	L01XM01
Molecular formula	C19H17F6N7O
Molecular weight	473.4
InChIKey	DYLUUSLLRIQKOE-UHFFFAOYSA-N

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

IUPAC name: 2-methyl-1-[[4-[6-(trifluoromethyl)-2-pyridinyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]amino]-1,3,5-triazin-2-yl]amino]propan-2-ol

ChEBI definition: A 1,3,5-triazine which is substituted by (2-hydroxy-2-methylpropyl)nitrilo, 6-(trifluoromethyl)pyridin-2-yl and [2-(trifluoromethyl)pyridin-4-yl]nitrilo groups at positions 2,4 and 6, respectively. It is an isocitrate dehydrogenase-2 (IDH2) inhibitor which has been approved for the treatment of adults with relapsed or refractory acute myeloid leukaemia (AML).

Pharmacological roles (ChEBI): antineoplastic agent, EC 1.1.1.42 (isocitrate dehydrogenase) inhibitor.

Also known as: Ag 221, AG-221, CC-90007 Free Base, Enasidenib, ENASIDENIB, ENASIDENIB MESYLATE, enasidenib

Parent form; salt/anhydrous children: CHEMBL3989931

Patent coverage: 921 distinct patent families (2,315 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 2,123 (92%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
IDH2	isocitrate dehydrogenase (NADP(+)) 2	Binding		0.2%	P48735

Broader ChEMBL bioactivity targets: 13 (assay-derived). Sample: Isocitrate dehydrogenase [NADP] cytoplasmic, Thromboxane A2 receptor, Muscarinic acetylcholine receptor M1, Prostaglandin G/H synthase 1, Adenosine receptor A1, Alpha-1A adrenergic receptor, Mu-type opioid receptor, Voltage-gated inwardly rectifying potassium channel KCNH2, Adenosine receptor A3, Vascular endothelial growth factor receptor 2.

Bioactivity

ChEMBL activities: 28 potent at pChembl ≥ 5 of 38 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
ADORA3	8.52	AC50	3	nM	CHEMBL_ACT_25198911
IDH2	8.05	IC50	9	nM	CHEMBL_ACT_18979536
IDH2	8.05	IC50	9	nM	CHEMBL_ACT_26147699
IDH2	7.96	IC50	11	nM	CHEMBL_ACT_25641355
ADORA3	7.92	IC50	12	nM	CHEMBL_ACT_29169112
IDH2	7.45	IC50	35.9	nM	CHEMBL_ACT_22786546
IDH2	7.43	IC50	37	nM	CHEMBL_ACT_29168891
IDH2	7	IC50	100	nM	CHEMBL_ACT_25641211
IDH2	6.75	IC50	179	nM	CHEMBL_ACT_25641225
IDH2	6.7	IC50	200	nM	CHEMBL_ACT_29154321
IDH2	6.58	IC50	262	nM	CHEMBL_ACT_18863519
IDH2	6.57	IC50	269.1	nM	CHEMBL_ACT_22786581
IDH2	6.51	IC50	310	nM	CHEMBL_ACT_20708214
IDH2	6.5	IC50	320	nM	CHEMBL_ACT_29154320
IDH2	6.47	IC50	340	nM	CHEMBL_ACT_18863500
IDH2	6.44	IC50	362	nM	CHEMBL_ACT_18863506
IDH2	6.36	IC50	438	nM	CHEMBL_ACT_25641259
IDH2	6.26	IC50	550	nM	CHEMBL_ACT_28266920
IDH1	6.17	IC50	677	nM	CHEMBL_ACT_26147698
IDH2	5.97	IC50	1080	nM	CHEMBL_ACT_20708234
ADORA1	5.89	AC50	1290	nM	CHEMBL_ACT_25202528
Q01827	5.75	AC50	1800	nM	CHEMBL_ACT_25197380
IDH2	5.75	IC50	1800	nM	CHEMBL_ACT_25641212
IDH1	5.3	IC50	4950	nM	CHEMBL_ACT_18979530
ABCB11	5.28	AC50	5300	nM	CHEMBL_ACT_25127080
TBXA2R	5.15	AC50	7087	nM	CHEMBL_ACT_25198097
PTGS1	5.04	AC50	9183	nM	CHEMBL_ACT_25205470
KCNH2	5.04	IC50	9020	nM	CHEMBL_ACT_25641217

Target pathways

Aggregated over 1 target gene(s): IDH2.

Top Reactome pathways

4 total, by targets touching each:

Pathway	Targets	Genes
Transcriptional activation of mitochondrial biogenesis	1	IDH2
Citric acid cycle (TCA cycle)	1	IDH2
Mitochondrial protein degradation	1	IDH2
Maturation of TCA enzymes and regulation of TCA cycle	1	IDH2

Dominant GO biological processes

GO term	Targets
carbohydrate metabolic process	1
glyoxylate cycle	1
tricarboxylic acid cycle	1
isocitrate metabolic process	1
2-oxoglutarate metabolic process	1
NADP+ metabolic process	1
NADP+ biosynthetic process	1
negative regulation of glial cell proliferation	1
negative regulation of glial cell migration	1
negative regulation of matrix metallopeptidase secretion	1

Indications & clinical

Indications

8 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
leukemia	3	MONDO:0005059	EFO:0000565
myelodysplastic syndrome	2	MONDO:0018881	EFO:0000198
acute myeloid leukemia	2	MONDO:0018874	EFO:0000222
myeloid leukemia	2	MONDO:0004643	MONDO:0004643
plasma cell myeloma	1	MONDO:0009693	EFO:0001378
liver disorder	1	MONDO:0005154	EFO:0001421
hematopoietic and lymphoid system neoplasm	1	MONDO:0002334	MONDO:0044881
neoplasm	1	MONDO:0005070	MONDO:0004992

Clinical trials

Total trials: 43.

Phase distribution

Phase	Trials
PHASE2	16
PHASE1	16
PHASE1/PHASE2	8
PHASE3	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03839771	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy, Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy
NCT02577406	PHASE3	COMPLETED	An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
NCT02677922	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy
NCT02813135	PHASE1/PHASE2	RECRUITING	European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
NCT03013998	PHASE1/PHASE2	RECRUITING	Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
NCT03383575	PHASE2	RECRUITING	Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome
NCT03683433	PHASE2	RECRUITING	Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation
NCT03728335	PHASE2	RECRUITING	Enasidenib (AG-221) Maintenance Post Allogeneic HCT in Patients With IDH2 Mutation
NCT03744390	PHASE2	ACTIVE_NOT_RECRUITING	IDH2 (AG 221) Inhibitor in Patients With IDH2 Mutated Myelodysplastic Syndrome
NCT03825796	PHASE2	ACTIVE_NOT_RECRUITING	CPX-351 Plus Enasidenib for Relapsed AML
NCT04203316	PHASE2	ACTIVE_NOT_RECRUITING	Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Patients With an IDH2 Mutation
NCT04774393	PHASE1/PHASE2	RECRUITING	Decitabine/Cedazuridine and Venetoclax in Combination With Ivosidenib or Enasidenib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
NCT05401097	PHASE2	RECRUITING	IDH Targeted/Non- Targeted vs Non-targeted/IDH-targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated AML Patients Not Candidates for Intensive Induction Therapy (I- DATA Study)
NCT05564390	PHASE2	RECRUITING	MYELOMATCH: A Screening Study to Assign People With Myeloid Cancer to a Treatment Study or Standard of Care Treatment Within myeloMATCH (MyeloMATCH Screening Trial)
NCT06176989	PHASE2	RECRUITING	Enasidenib in IDH2-Mutated Malignant Sinonasal and Skull Base Tumors
NCT06240754	PHASE2	RECRUITING	Enasidenib for Patients With Clonal Cytopenia of Undetermined Significance and Mutations in IDH2A Decentralized Trial
NCT06577441	PHASE2	RECRUITING	Testing the Addition of an IDH2 Inhibitor, Enasidenib, to Usual Treatment (Cedazuridine-Decitabine) for Higher-Risk Myelodysplastic Syndrome (MDS) With IDH2 Mutation (A MyeloMATCH Treatment Trial)
NCT06672146	PHASE2	RECRUITING	Comparing New Treatments for People With Newly Diagnosed Acute Myeloid Leukemia That Has an IDH2 Gene Change (A MyeloMATCH Treatment Trial)
NCT06756308	PHASE2	RECRUITING	A Study of Enasidenib in People With T-Cell Lymphoma
NCT01915498	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation
NCT02273739	PHASE1/PHASE2	COMPLETED	Study of Orally Administered Enasidenib (AG-221) in Adults With Advanced Solid Tumors, Including Glioma, or Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation
NCT03732703	PHASE1/PHASE2	COMPLETED	Myeloma-Developing Regimens Using Genomics (MyDRUG)
NCT03881735	PHASE2	WITHDRAWN	Enasidenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia With an IDH2 Gene Mutation
NCT04092179	PHASE1/PHASE2	TERMINATED	Study of Enasidenib and Venetoclax in IDH2-Mutated Blood Cancers
NCT04281498	PHASE2	COMPLETED	Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation
NCT04522895	PHASE2	COMPLETED	IDH2-Post-Allo-Trial for Patients with IDH2-mut Myeloid Neoplasms After Allo-SCT
NCT02632708	PHASE1	ACTIVE_NOT_RECRUITING	Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) With an IDH1 and/or IDH2 Mutation
NCT05010772	PHASE1	RECRUITING	Decitabine Alone or in Combination With Venetoclax, Gilteritinib, Enasidenib, or Ivosidenib as Maintenance Therapy for the Treatment of Acute Myeloid Leukemia in Remission
NCT05756777	PHASE1	RECRUITING	A Study of Gilteritinib in Combination With Ivosidenib or Enasidenib in People With Acute Myeloid Leukemia (AML)
NCT02387866	PHASE1	COMPLETED	PK and Safety Study of AG-221 in Healthy Male Japanese Subjects and Healthy Male Caucasian Subjects
NCT02443168	PHASE1	COMPLETED	Radiolabeled Study of AG-221 in Healthy Male Subjects.
NCT03290443	PHASE1	COMPLETED	A Study to Assess the Pharmacokinetics of Enasidenib (CC-90007) in Subjects With Moderate and Severe Hepatic Impairment.
NCT03515512	PHASE1	COMPLETED	IDH2 Inhibition Using Enasidenib as Maintenance Therapy for IDH2-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation
NCT03720366	PHASE1	COMPLETED	A Study of Perpetrator Drug Interactions of Enasidenib in AML Patients
NCT03878524	PHASE1	TERMINATED	Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial
NCT04075747	PHASE1	COMPLETED	A Phase 1b Master Trial to Investigate CPX-351 in Subjects With Previously Untreated Acute Myeloid Leukemia
NCT04310527	PHASE1	COMPLETED	Bioavailability of Enasidenib (CC-90007) Sprinkle Formulation Relative to the Reference Tablet Formulation and Effect of Food on the Pharmacokinetics of Sprinkle Formulation in Healthy Adults
NCT04573582	PHASE1	COMPLETED	Pharmacokinetics of Enasidenib (CC-90007) in Participants With Mild, Moderate and Severe Hepatic Impairment
NCT04655391	PHASE1	WITHDRAWN	Glasdegib-Based Treatment Combinations for the Treatment of Patients With Relapsed Acute Myeloid Leukemia Who Have Undergone Hematopoietic Cell Transplantation
NCT04955938	PHASE1	WITHDRAWN	A Study of Fedratinib With IDH Inhibition in Advanced-Phase, IDH-Mutated Ph-Negative Myeloproliferative Neoplasms

Clinical evidence (CIViC)

Variant × indication × effect (2 predictive associations from 3 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
IDH2 Mutation	Acute Myeloid Leukemia	Sensitivity/Response	Enasidenib	CIViC A	EID5069 +1
IDH2 R140	Acute Myeloid Leukemia	Sensitivity/Response	Enasidenib	CIViC D	EID10292

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

5 molecules share ≥1 primary target. Top 5 by shared-target count:

Molecule	Source	Status	Shared targets
IVOSIDENIB	ChEMBL + PubChem	Phase 4 (approved)	IDH2
OLUTASIDENIB	ChEMBL + PubChem	Phase 4 (approved)	IDH2
VORASIDENIB	ChEMBL + PubChem	Phase 4 (approved)	IDH2
CRELOSIDENIB	ChEMBL	Phase 2	IDH2
RANOSIDENIB	ChEMBL	Phase 2	IDH2