QUIZARTINIB DIHYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H32N6O4S.2ClH
Molecular Weight	633.589
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of QUIZARTINIB DIHYDROCHLORIDE

Structure Search

SMILES

Cl.Cl.CC(C)(C)C1=CC(NC(=O)NC2=CC=C(C=C2)C3=CN4C(SC5=C4C=CC(OCCN6CCOCC6)=C5)=N3)=NO1

InChI

InChIKey=DHYPGRVMIOATAE-UHFFFAOYSA-N

InChI=1S/C29H32N6O4S.2ClH/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34;;/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36);2*1H

HIDE SMILES / InChI

Molecular Formula	C29H32N6O4S
Molecular Weight	560.667
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://adisinsight.springer.com/drugs/800025852
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19654408 | https://www.ncbi.nlm.nih.gov/pubmed/23497317

Quizartinib (AC220) is an orally bioavailable, small molecule receptor tyrosine kinase inhibitor that is being developed by Daiichi Sankyo Company (previously Ambit Biosciences) and Astellas Pharma as a treatment for acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and advanced solid tumours. The highest affinity target identified for Quizartinib was FLT3. The only other kinases with binding constants within 10-fold that for FLT3 were the closely related receptor tyrosine kinases KIT, PDGFRA, PDGFRB, RET, and CSF1R. Kinase inhibition of (mutant) KIT, PDGFR and FLT3 isoforms by quizartinib leads to potent inhibition of cellular proliferation and induction of apoptosis in in vitro leukemia models as well as in native leukemia blasts treated ex vivo.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Tyrosine-protein kinase receptor FLT3 42 Target ID: CHEMBL1974 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408 \| https://www.ncbi.nlm.nih.gov/pubmed/19754199 \| https://www.ncbi.nlm.nih.gov/pubmed/23497317	Inhibitor 8504	1.6 nM [Kd]
Stem cell growth factor receptor 57 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23497317 \| https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8504	4.8 nM [Kd]
Platelet-derived growth factor receptor alpha 33 Target ID: CHEMBL2007 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23497317 \| https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8504	11.0 nM [Kd]
Platelet-derived growth factor receptor beta 56 Target ID: CHEMBL1913 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8504	7.7 nM [Kd]
Tyrosine-protein kinase receptor RET 16 Target ID: CHEMBL2041 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8504	9.9 nM [Kd]
Macrophage colony stimulating factor receptor 24 Target ID: CHEMBL1844 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8504	12.0 nM [Kd]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 141 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 665	Unknown Approved Use Unknown
Acute lymphoblastic leukemia 27 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 665	Unknown Approved Use Unknown
Myelodysplastic syndromes 61 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 665	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
103.9 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31173645/	26.5 mg single, oral dose: 26.5 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
400 ng × eq/g EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/27460866	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
9626 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31173645/	26.5 mg single, oral dose: 26.5 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
10000 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24002496	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
102 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/31173645/	26.5 mg single, oral dose: 26.5 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1.5 day EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24002496	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% REVIEW https://pubmed.ncbi.nlm.nih.gov/31916418/	26.5 mg single, oral dose: 26.5 mg route of administration: Oral experiment type: SINGLE co-administered:		QUIZARTINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
90 mg 1 times / day multiple, oral MTD Dose: 90 mg, 1 times / day Route: oral Route: multiple Dose: 90 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/	unhealthy, Median age 49.5 years Health Status: unhealthy Age Group: Median age 49.5 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/	Other AEs: Fatigue, Dysgeusia... Other AEs: Fatigue (62.5%) Dysgeusia (25%) Nausea (37.5%) Vomiting (25%) Edema peripheral (25%) Peripheral sensory neuropathy (12.5%) Anemia (25%) Neutropenia (25%) Electrocardiogram QT prolonged (12.5%) Tumor pain (12.5%) Abdominal distension (12.5%) Leukopenia (12.5%) Thrombocytopenia (12.5%) Hyperglycemia (25%) Dyspnea (12.5%) Pain in extremity (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/
250 mg 1 times / day multiple, oral Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy, Median age 52 years Health Status: unhealthy Age Group: Median age 52 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	Other AEs: Fatigue, Photosensitivity... Other AEs: Fatigue (grade 3, 4%) Photosensitivity (grade 3, 4%) Thrombocytopenia (grade 3, 4%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/
300 mg 1 times / day multiple, oral Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy, Median age 52 years Health Status: unhealthy Age Group: Median age 52 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	DLT: Electrocardiogram QTc interval prolonged... Dose limiting toxicities: Electrocardiogram QTc interval prolonged (grade 3, 38%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/
200 mg 1 times / day multiple, oral MTD Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy, Median age 52.4 years Health Status: unhealthy Age Group: Median age 52.4 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	DLT: Electrocardiogram QTc interval prolonged... Dose limiting toxicities: Electrocardiogram QTc interval prolonged (grade 3, 24%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/31175001/	unhealthy, Median age 55 years Health Status: unhealthy Age Group: Median age 55 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/31175001/	Disc. AE: Pneumonia, Intracranial haemorrhage... Other AEs: Nausea, Fatigue... AEs leading to discontinuation/dose reduction: Pneumonia (2%) Intracranial haemorrhage (2%) Graft versus host disease (2%) Septic shock (2%) QT interval prolonged (grade 2, 1%) QT interval prolonged (5%) QT interval prolonged (9%) Other AEs: Nausea (grade 3, 2%) Fatigue (grade 3, 8%) Thrombocytopenia (grade 3, 5%) Thrombocytopenia (grade 4, 30%) Thrombocytopenia (grade 5, <1%) Pyrexia (grade 3, 2%) Musculoskeletal pain (grade 3, 4%) Anaemia (grade 3, 29%) Anaemia (grade 4, 1%) Febrile neutropenia (grade 3, 28%) Febrile neutropenia (grade 4, 2%) Neutropenia (grade 3, 5%) Neutropenia (grade 4, 27%) Vomiting (grade 3, 3%) Hypokalaemia (grade 3, 11%) Hypokalaemia (grade 4, 1%) Diarrhoea (grade 3, 2%) Electrocardiogram QT prolonged (grade 3, 4%) Cough (grade 3, <1%) Rash (grade 3, 2%) Abdominal pain (grade 3, 2%) Headache (grade 3, <1%) Septic shock (grade 3, 11%) Septic shock (grade 4, 6%) Septic shock (grade 5, 2%) Oedema peripheral (grade 3, 3%) Decreased appetite (grade 3, 2%) Dyspnoea (grade 3, 5%) Dyspnoea (grade 4, <1%) White blood cell count decreased (grade 3, 5%) White blood cell count decreased (grade 4, 12%) Stomatitis (grade 3, 2%) Stomatitis (grade 4, <1%) Pneumonia (grade 3, 7%) Pneumonia (grade 4, 1%) Pneumonia (grade 5, 4%) ALT increased (grade 3, 4%) Hypotension (grade 3, 3%) Hypotension (grade 4, <1%) Graft versus host disease (grade 3, 3%) Graft versus host disease (grade 4, 1%) Graft versus host disease (grade 5, 1%) Hypocalcaemia (grade 3, <1%) Petechiae (grade 3, 1%) Weight decreased (grade 3, 1%) Hypophosphataemia (grade 3, 4%) Hypophosphataemia (grade 4, <1%) Hyponatremia (grade 3, 3%) Hyponatremia (grade 4, <1%) Urinary tract infection (grade 3, 4%) Urinary tract infection (grade 4, <1%) Upper respiratory tract infection (grade 3, 2%) Cellulitis (grade 3, 3%) Hyperglycaemia (grade 3, 1%) Hyperglycaemia (grade 4, 1%) Leukocytosis (grade 3, 2%) Leukocytosis (grade 4, 1%) Leukocytosis (grade 5, <1%) Acute renal failure (grade 3, 1%) Acute renal failure (grade 4, <1%) Acute renal failure (grade 5) Pancytopenia (grade 3, 5%) Syncope (grade 3, 4%) Clostridioides difficile infection (grade 3, 2%) Clostridioides difficile infection (grade 4, <1%) Device related infection (grade 3, 3%) Lymphocyte count decreased (grade 3, 2%) Lymphocyte count decreased (grade 4, 1%) Intracranial haemorrhage (grade 4, 1%) Intracranial haemorrhage (grade 5, 2%) Pneumonia fungal (grade 3, 2%) Respiratory distress (grade 3, 1%) Respiratory distress (grade 4, <1%) Respiratory distress (grade 5, 1%) Sources: https://pubmed.ncbi.nlm.nih.gov/31175001/
135 mg 1 times / day multiple, oral Dose: 135 mg, 1 times / day Route: oral Route: multiple Dose: 135 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/	unhealthy, Median age 56 years Health Status: unhealthy Age Group: Median age 56 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/	DLT: Pancytopenia, Electrocardiogram QT prolonged... Dose limiting toxicities: Pancytopenia (grade 3, 20%) Electrocardiogram QT prolonged (grade 3, 20%) Febrile neutropenia (20%) Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/
450 mg 1 times / day multiple, oral Highest studied dose Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy, Median age 57.8 years Health Status: unhealthy Age Group: Median age 57.8 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	Other AEs: Electrocardiogram QTc interval prolonged... Other AEs: Electrocardiogram QTc interval prolonged (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/
73.5 mg 1 times / day multiple, oral Dose: 73.5 mg, 1 times / day Route: oral Route: multiple Dose: 73.5 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy, Median age 64 years Health Status: unhealthy Age Group: Median age 64 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	Other AEs: Vomiting, Anorexia... Other AEs: Vomiting (grade 3, 3%) Anorexia (grade 3, 3%) Fatigue (grade 3, 3%) Anemia (grade 3, 6%) Hypocalcemia (grade 3, 3%) Pyrexia (grade 3, 3%) Pancytopenia (grade 3, 3%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/
316.7 mg 1 times / day multiple, oral Dose: 316.7 mg, 1 times / day Route: oral Route: multiple Dose: 316.7 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	unhealthy Health Status: unhealthy Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/	Other AEs: Anemia, Eyelid edema... Other AEs: Anemia (grade 3, 6%) Eyelid edema (grade 3, 6%) Hypoalbuminemia (grade 3, 6%) Lung infection (grade 3, 6%) Sources: https://pubmed.ncbi.nlm.nih.gov/24002496/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946			inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 P-gp 1741	CYP3A 220 CYP3A5 446 P-gp 2052

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 985	inhibitor 4027 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706835/ Page: -	yes
P-gp 1932	inhibitor 4027 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A5 446	substrate 4014 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes
P-gp 2052	substrate 4014 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes
CYP3A 220	substrate 4014 Sources: https://www.fda.gov/media/124897/download#page=13 Page: -	yes	yes (co-administration study) Comment: The PBPK results indicated that coadministration of rifampin, a strong CYP3A inducer, with quizartinib would result in an approximately 72% decrease in quizartinib exposure and an approximately 66% decrease in AC886 exposure (AUCinf) Sources: https://www.fda.gov/media/124897/download#page=13 Page: -
CYP3A4 1946	substrate 4014 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710528/ Page: -	yes	yes (co-administration study) Comment: Steady‐state PK simulation demonstrated ~2‐fold increase of both steady–state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710528/ Page: -

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -

PubMed

Title	Date	PubMed
BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.	2014-10	25053825
Comprehensive analysis of kinase inhibitor selectivity.	2011-10-30	22037378
Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia.	2011-10-27	21970471
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010-11-24	21095574
Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor.	2009-12-10	19754199
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).	2009-10-01	19654408

Patents

Sample Use Guides

In Vivo Use Guide

60 mg daily was selected as the highest dose for continuous daily administration based on Phase 2 study data in relapsed or refractory acute myeloid leukaemia patients. Quizartinib was well tolerated at daily doses ≤ 200 mg/day in patients with relapsed or refractory acute myeloid leukaemia patients (Phase I study).

Route of Administration: Oral

In Vitro Use Guide

Both of the FLT3-ITD cell lines, MV4-11 and MOLM-14, were exquisitely sensitive to quizartinib treatment with cell viability IC50 values of 0.1 to 0.3 nmol/L measured at 72 hours. Interestingly, while an IC50 of 0.4 nmol/L could be measured after 72 hours in SEM-K2 cells, complete loss of viability required 5 to 7 days. In contrast, minimal or no loss of viability was observed in the FLT3-WT–expressing RS4;11 and THP-1 cells, even following 7 days of quizartinib treatment, consistent with reports that these lines are not dependent on FLT3 signaling for sustained cell growth

Substance Class	Chemical Created by `admin` on `Mon Mar 31 19:56:51 GMT 2025` Edited by `admin` on `Mon Mar 31 19:56:51 GMT 2025`
Record UNII	WK7Q6ZIZ10
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

QUIZARTINIB DIHYDROCHLORIDE

Official Name

English

VANFLYTA

Preferred Name

English

N-(5-TERT-BUTYL-ISOXAZOL-3-YL)-N'-(4-(7-(2-(MORPHOLIN-4-YLETHOXY)IMIDAZO(2,1-B)(1,3)BENZOTHIAZOL-2-YL)PHENYL)UREA DIHYDROCHLORIDE

Common Name

English

QUIZARTINIB HYDROCHLORIDE

Common Name

English

N-(5-(1,1-DIMETHYLETHYL)ISOXAZOL-3-YL)-N'-(4-(7-(2-(MORPHOLIN-4-YL)ETHOXY)IMIDAZO(2,1-B)BENZOTHIAZOL-2-YL)PHENYL)UREA DIHYDROCHLORIDE

Systematic Name

English

AC010220.2HCL

Code

English

QUIZARTINIB DIHYDROCHLORIDE [USAN]

Common Name

English

N-(5-TERT-BUTYLISOXAZOL-3-YL)-N'-(4-(7-(2-(MORPHOLIN-4-YL)ETHOXY) IMIDAZO(2,1-B)(1,3)BENZOTHIAZOL-2-YL)PHENYL)UREA DI-HYDROCHLORIDE SALT

Systematic Name

English

AC220 2HCL

Code

English

AC-010220 DIHYDROCHLORIDE

Code

English

AC-220 DIHYDROCHLORIDE

Code

English

UREA, N-(5-(1,1-DIMETHYLETHYL)-3-ISOXAZOLYL)-N'-(4-(7-(2-(4-MORPHOLINYL) ETHOXY)IMIDAZO(2,1-B)BENZOTHIAZOL-2-YL)PHENYL)-, HYDROCHLORIDE (1:2)

Systematic Name

English

QUIZARTINIB HYDROCHLORIDE [JAN]

Common Name

English

AC010220 2HCL

Code

English

Quizartinib dihydrochloride [WHO-DD]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

MM Test