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

SMILES

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

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	Inhibitor 8,504	1.6 nM [Kd]
Stem cell growth factor receptor 57	Inhibitor 8,504	4.8 nM [Kd]
Platelet-derived growth factor receptor alpha 33	Inhibitor 8,504	11.0 nM [Kd]
Platelet-derived growth factor receptor beta 56	Inhibitor 8,504	7.7 nM [Kd]
Tyrosine-protein kinase receptor RET 16	Inhibitor 8,504	9.9 nM [Kd]
Macrophage colony stimulating factor receptor 24	Inhibitor 8,504	12.0 nM [Kd]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 141	Primary	Phase III 665	Unknown
Acute lymphoblastic leukemia 27	Primary	Phase III 665	Unknown
Myelodysplastic syndromes 61	Primary	Phase III 665	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
103.9 ng/mL	26.5 mg single, oral		QUIZARTINIB plasma	Homo sapiens
400 ng × eq/g	60 mg single, oral		QUIZARTINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
9626 ng × h/mL	26.5 mg single, oral		QUIZARTINIB plasma	Homo sapiens
10000 ng × h/mL	300 mg single, oral		QUIZARTINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
102 h	26.5 mg single, oral		QUIZARTINIB plasma	Homo sapiens
1.5 day	300 mg single, oral		QUIZARTINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	26.5 mg single, oral		QUIZARTINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years	Other AEs: Fatigue, Dysgeusia...
250 mg 1 times / day multiple, oral	unhealthy, Median age 52 years	Other AEs: Fatigue, Photosensitivity...
300 mg 1 times / day multiple, oral	unhealthy, Median age 52 years	DLT: Electrocardiogram QTc interval prolonged...
200 mg 1 times / day multiple, oral MTD	unhealthy, Median age 52.4 years	DLT: Electrocardiogram QTc interval prolonged...
60 mg 1 times / day multiple, oral	unhealthy, Median age 55 years	Disc. AE: Pneumonia, Intracranial haemorrhage... Other AEs: Nausea, Fatigue...

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AEs

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AE	Significance	Dose	Population
Abdominal distension	12.5%	90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years
Dyspnea	12.5%	90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years
Electrocardiogram QT prolonged	12.5%	90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years
Leukopenia	12.5%	90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years
Pain in extremity	12.5%	90 mg 1 times / day multiple, oral MTD	unhealthy, Median age 49.5 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946			inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 910 P-gp 1,741	CYP3A 220 CYP3A5 446 P-gp 2,052

Drug as perpetrator

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Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 985	inhibitor 4,027	yes
P-gp 1,932	inhibitor 4,027	yes

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A5 446	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes
CYP3A 220	substrate 4,014	yes	yes (co-administration study)
CYP3A4 1,946	substrate 4,014	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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PubMed

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Title	Date	PubMed
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

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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

Show entries

Name

Type

Language

quizartinib [INN]

Preferred Name

English

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

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

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Show entries

Code System

Code

Type

Description

FDA UNII

7LA4O6Q0D3

PRIMARY

WIKIPEDIA

QUIZARTINIB

PRIMARY

CAS

950769-58-1

PRIMARY

CHEBI

90217

PRIMARY

DRUG CENTRAL

5341

PRIMARY

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ACTIVE MOIETY


					7LA4O6Q0D3

QUIZARTINIB

SALT/SOLVATE (PARENT)


					PLM3B7HQ6U

QUIZARTINIB MONOHYDROCHLORIDE

SALT/SOLVATE (PARENT)


					WK7Q6ZIZ10

QUIZARTINIB DIHYDROCHLORIDE

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator