QUIZARTINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C29H32N6O4S
Molecular Weight	560.667
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)(C)C1=CC(NC(=O)NC2=CC=C(C=C2)C3=CN4C(SC5=CC(OCCN6CCOCC6)=CC=C45)=N3)=NO1

InChI

InChIKey=CVWXJKQAOSCOAB-UHFFFAOYSA-N

InChI=1S/C29H32N6O4S/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)

HIDE SMILES / InChI

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 43 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 8297	1.6 nM [Kd]
Stem cell growth factor receptor 53 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23497317 \| https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8297	4.8 nM [Kd]
Platelet-derived growth factor receptor alpha 30 Target ID: CHEMBL2007 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23497317 \| https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8297	11.0 nM [Kd]
Platelet-derived growth factor receptor beta 56 Target ID: CHEMBL1913 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8297	7.7 nM [Kd]
Tyrosine-protein kinase receptor RET 14 Target ID: CHEMBL2041 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8297	9.9 nM [Kd]
Macrophage colony stimulating factor receptor 24 Target ID: CHEMBL1844 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19654408	Inhibitor 8297	12.0 nM [Kd]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 136 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 656	Unknown Approved Use Unknown
Acute lymphoblastic leukemia 27 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 656	Unknown Approved Use Unknown
Myelodysplastic syndromes 58 Sources: http://adisinsight.springer.com/drugs/800025852	Primary	Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
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
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: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
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: 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 n = 8 Health Status: unhealthy Condition: solid tumors Age Group: Median age 49.5 years Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/	Other AEs: Hyperglycemia, Fatigue... Other AEs: Hyperglycemia (25%) 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%) Dyspnea (12.5%) Pain in extremity (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/30081867/
250 mg 1 times / day multiple, oral (mean) 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 n = 25 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: Median age 52 years Sex: M+F Population Size: 25 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 n = 8 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: Median age 52 years Sex: M+F Population Size: 8 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 n = 17 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: Median age 52.4 years Sex: M+F Population Size: 17 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 n = 241 Health Status: unhealthy Condition: acute myeloid leukaemia Age Group: Median age 55 years Sex: M+F Population Size: 241 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 n = 5 Health Status: unhealthy Condition: solid tumors Age Group: Median age 56 years Sex: M+F Population Size: 5 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 n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: Median age 57.8 years Sex: M+F Population Size: 6 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 (mean) 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 n = 35 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: Median age 64 years Sex: M+F Population Size: 35 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 (mean) 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 n = 16 Health Status: unhealthy Condition: acute myeloid leukemia Sex: M+F Population Size: 16 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 1737			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 P-gp 1461	CYP3A 191 CYP3A5 395 P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 773	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706835/ Page: -	yes
P-gp 1650	inhibitor 3277 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A5 395	substrate 3367 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes
P-gp 1537	substrate 3367 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -	yes
CYP3A 191	substrate 3367 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 1737	substrate 3367 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 1647	inhibitor 1626 Sources: https://www.fda.gov/media/124897/download#page=39 Page: -

PubMed

Title	Date	PubMed
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 Dec 10	19754199
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).	2009 Oct 1	19654408
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
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 Oct 27	21970471
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
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 Oct	25053825

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

Name

Type

Language

QUIZARTINIB

Official Name

English

AC010220

Code

English

AC-010220

Code

English

1-(5-TERT-BUTYL-1,2-OXAZOL-3-YL)-3-(4-(7-(2-(MORPHOLIN-4-YL)ETHOXY)IMIDAZO(2,1-B)(1,3)BENZOTHIAZOL-2-YL)PHENYL)UREA

Systematic Name

English

AC220

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)-

Common Name

English

AC-220

Code

English

Quizartinib [WHO-DD]

Common Name

English

ASP-2689

Code

English

QUIZARTINIB [MI]

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

Systematic Name

English

QUIZARTINIB [USAN]

Common Name

English

quizartinib [INN]

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

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825