ENASIDENIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H17F6N7O
Molecular Weight	473.375
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(O)CNC1=NC(NC2=CC=NC(=C2)C(F)(F)F)=NC(=N1)C3=CC=CC(=N3)C(F)(F)F

InChI

InChIKey=DYLUUSLLRIQKOE-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: https://newdrugapprovals.org/2016/04/20/enasidenib-ag-221/
Curator's Comment: Description was created based on several sources, including http://www.agios.com/patients-trials.php http://www.selleckchem.com/products/ag-221-enasidenib.html http://adisinsight.springer.com/drugs/800038591

Enasidenib, aslo 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. Enasidenib is an orally available, selective, potent inhibitor of the mutated IDH2 protein, making it a highly targeted investigational medicine for the potential treatment of patients with cancers that harbor an IDH2 mutation. Enasidenib has received orphan drug and fast track designations from the U.S. FDA. Enasidenib mesylate is in phase II clinical trials for Solid tumours and phase III clinical trials for the treatment of acute myeloid leukaemia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Isocitrate dehydrogenase [NADP], mitochondrial 5 Target ID: P48735 Gene ID: 3418.0 Gene Symbol: IDH2 Target Organism: Homo sapiens (Human) Sources: https://newdrugapprovals.org/2016/04/20/enasidenib-ag-221/ \| https://www.ncbi.nlm.nih.gov/pubmed/26590767	Inhibitor 8297		12.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
acute myeloid leukemia 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf	Primary		Approved 8429	IDHIFA Approved Use IDHIFA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. Launch Date 2017
Acute myeloid leukemia 136 Sources: https://clinicaltrials.gov/ct2/show/NCT02577406	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
822 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30386625	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ENASIDENIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
13 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
49500 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30386625	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ENASIDENIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
25.5 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30386625	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		ENASIDENIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
137 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
1.5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf	100 mg 1 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		ENASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
650 mg 1 times / day multiple, oral Highest studied dose Dose: 650 mg, 1 times / day Route: oral Route: multiple Dose: 650 mg, 1 times / day Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/	unhealthy, adult n = 5 Health Status: unhealthy Condition: myeloid leukemia Age Group: adult Sex: unknown Population Size: 5 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/	Other AEs: Abdominal distension, Diarrhea... Other AEs: Abdominal distension (1 patient) Diarrhea (1 patient) Fatigue (1 patient) Hyperbilirubinemia (3 patients) Rash (1 patient) Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572791/
100 mg 1 times / day multiple, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 5	unhealthy, adult n = 214 Health Status: unhealthy Condition: myeloid leukemia Age Group: adult Sex: unknown Population Size: 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 5	Disc. AE: Leukocytosis... Other AEs: Nausea, Diarrhea... AEs leading to discontinuation/dose reduction: Leukocytosis (1%) Other AEs: Nausea (all grades, 50%) Diarrhea (all grades, 43%) Vomiting (all grades, 34%) Decreased appetite (all grades, 34%) Tumor lysis syndrome (all grades, 6%) Differentiation syndrome (all grades, 14%) Leukocytosis (all grades, 12%) Dysgeusia (all grades, 12%) Nausea (grade 3-4, 5%) Diarrhea (grade 3-4, 8%) Vomiting (grade 3-4, 2%) Decreased appetite (grade 3-4, 4%) Tumor lysis syndrome (grade 3-4, 6%) Differentiation syndrome (grade 3-4, 7%) Leukocytosis (grade 3-4, 6%) Bilirubin total increased (all grades, 81%) Calcium decreased (all grades, 74%) Potassium decreased (all grades, 41%) Blood phosphorus decreased (all grades, 27%) Differentiation syndrome (4%) Leukocytosis (3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 5
100 mg 1 times / day multiple, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 6	unhealthy, adult n = 214 Health Status: unhealthy Condition: myeloid leukemia Age Group: adult Sex: unknown Population Size: 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 6	Other AEs: Bilirubin total increased, Calcium decreased... Other AEs: Bilirubin total increased (grade 3-4, 15%) Calcium decreased (grade 3-4, 8%) Potassium decreased (grade 3-4, 15%) Blood phosphorus decreased (grade 3-4, 8%) Hyperbilirubinemia (3.7%) Hyperbilirubinemia (1.4%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209606s000lbl.pdf Page: 6
100 mg 1 times / day multiple, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45	unhealthy, adult n = 214 Health Status: unhealthy Condition: myeloid leukemia Age Group: adult Sex: unknown Population Size: 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45	Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5, 4.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45
100 mg 1 times / day multiple, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45	unhealthy, adult n = 214 Health Status: unhealthy Condition: myeloid leukemia Age Group: adult Sex: unknown Population Size: 214 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45	Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5, 11.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf#page=22 Page: 45

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587 inducer 781	substrate 1037 inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478 UGT1A1 204 P-gp 1461 BCRP 699 OAT1 599 OATP1B1 788 OATP1B3 706 OCT2 647 MRP2 383 OAT3 642	P-gp 1537 BCRP 561 MRP2 205 OAT1 326 OAT3 339 OATP1B1 406 OATP1B3 350 OCT2 355 CYP1A2 1054 CYP2B6 664 CYP2C8 693 UGT1A1 418 UGT1A3 422 UGT1A4 347 UGT1A9 380 CYP2C19 991	CYP2B6 547

Drug as perpetrator

Target	Modality	Activity	Metabolite
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no	AGI-16903 2
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no	AGI-16903 2
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no	AGI-16903 2
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
OATP1B3 715	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes

Drug as victim

Target	Modality	Activity	Metabolite
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP2B6 664	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C19 991	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
UGT1A1 418	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
UGT1A3 422	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
UGT1A3 422	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2
UGT1A4 347	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209606Orig1s000MultidisciplineR.pdf Page: 62.0	yes	AGI-16903 2

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:145374	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:145374
ChemicalBook	CB53044318	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB53044318
MolPort	MolPort-042-676-239	https://www.molport.com/shop/molecule-link/MolPort-042-676-239
ZINC	ZINC000222731806	http://zinc15.docking.org/substances/ZINC000222731806

PubMed

Title	Date	PubMed
[Progress in molecularly targeted therapies for acute myeloid leukemia].	2015 Feb	25765792
IDH2 inhibition in AML: Finally progress?	2015 Jun-Sep	26590767
The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors.	2016	27292784

Patents

Sample Use Guides

In Vivo Use Guide

Continuous 28-day cycles of Enasidenib (AG 221) 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.

Route of Administration: Oral

In Vitro Use Guide

Unknown

Name

Type

Language

ENASIDENIB

Official Name

English

ENASIDENIB [MI]

Common Name

English

AG-221

Code

English

2-METHYL-1-(4-(6-(TRIFLUOROMETHYL)PYRIDIN-2-YL)-6-(2-(TRIFLUOROMETHYL)PYRIDIN-4-YLAMINO)-1,3,5-TRIAZIN-2-YLAMINO)PROPAN-2-OL

Systematic Name

English

ENASIDENIB [USAN]

Common Name

English

Enasidenib [WHO-DD]

Common Name

English

2-PROPANOL, 2-METHYL-1-((4-(6-(TRIFLUOROMETHYL)-2-PYRIDINYL)-6-((2-(TRIFLUOROMETHYL)-4-PYRIDINYL)AMINO)-1,3,5-TRIAZIN-2-YL)AMINO)-

Systematic Name

English

enasidenib [INN]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

434514