DASATINIB ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H26ClN7O2S
Molecular Weight	488.006
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC1=NC(NC2=NC=C(S2)C(=O)NC3=C(Cl)C=CC=C3C)=CC(=N1)N4CCN(CCO)CC4

InChI

InChIKey=ZBNZXTGUTAYRHI-UHFFFAOYSA-N

InChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27)

HIDE SMILES / InChI

Description

Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. It’s used for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia with resistance or intolerance to prior therapy. Also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020. Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
SRC 5	Inhibitor 8,297
Stem cell growth factor receptor 53	Inhibitor 8,297
Ephrin type-A receptor 2 6	Inhibitor 8,297
Platelet-derived growth factor receptor beta 56	Inhibitor 8,297
Tyrosine-protein kinase ABL 29	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) 3	Primary		Approved 8,429	SPRYCEL
Acute lymphoblastic leukemia 27	Primary		Approved 8,429	SPRYCEL

C_max

Value	Dose	Co-administered	Analyte	Population
82.2 ng/mL	100 mg 1 times / day steady-state, oral		DASATINIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
397 ng × h/mL	100 mg 1 times / day steady-state, oral		DASATINIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
3 h	100 mg 1 times / day steady-state, oral		DASATINIB plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
6%			DASATINIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6	DLT: Dehydration, Hyponatremia... Other AEs: Fatigue, Nausea...
160 mg 2 times / day steady, oral Highest studied dose	unhealthy, 32-81 years n = 4	DLT: Rash, Lethargy... Other AEs: Nausea, Fatigue...
120 mg 2 times / day steady, oral MTD	unhealthy, 32-81 years n = 9	DLT: Tumor lysis syndrome... Other AEs: Nausea, Fatigue...
70 mg 2 times / day steady, oral MTD	unhealthy, 32-81 years n = 5	Other AEs: Nausea, Anorexia...
50 mg 2 times / day steady, oral Recommended	unhealthy, 32-81 years n = 3	Other AEs: Nausea, Fatigue...

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AEs

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AE	Significance	Dose	Population
Anorexia	grade 1-2, 1 patient	90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6
Diarrhea	grade 1-2, 1 patient	90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6
Headache	grade 1-2, 1 patient	90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6
Nausea	grade 1-2, 1 patient	90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6
Lethargy	grade 1-2, 2 patients	90 mg 2 times / day steady, oral Higher than recommended	unhealthy, 32-81 years n = 6

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inhibitor 1,587 inducer 781	inhibitor 1,767 inducer 389	inhibitor 1,852 inducer 97	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A5 73 P-gp 1,461	FMO3 67	CYP2C19 293 CYP1A2 701 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 1,692	inhibitor 3,277	no [IC50 >50 uM]
CYP2B6 1,001	inhibitor 3,277	no [IC50 >50 uM]
CYP2C19 1,553	inhibitor 3,277	no [IC50 >50 uM]
CYP2D6 1,891	inhibitor 3,277	no [IC50 >50 uM]
CYP2E1 970	inhibitor 3,277	no [IC50 >50 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
FMO3 67	substrate 3,367	yes
CYP3A4 1,737	substrate 3,367	yes		yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

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Title	Date	PubMed
Two new agents effective in Gleevec-resistant CML.	2004 Dec	15864854
A single nucleotide polymorphism in the coding region of ABL and its effects on sensitivity to imatinib.	2005 Nov	16151465
Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib.	2005 Oct 1	16203792
[Tyrosine kinase inhibitors in the therapy of chronic myeloid leukaemia].	2006	17013368
Dasatinib induces a response in malignant thymoma.	2006 Dec 1	17135636

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended starting dosage of SPRYCEL (dasatinib) for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of SPRYCEL for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. SPRYCEL can be taken with or without a meal, either in the morning or in the evening.

Route of Administration: Oral

In Vitro Use Guide

Unknown

Show entries

Name

Type

Language

DASATINIB ANHYDROUS

Common Name

English

BMS-354825

Code

English

5-THIAZOLECARBOXAMIDE, N-(2-CHLORO-6-METHYLPHENYL)-2-((6-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-2-METHYL-4-PYRIMIDINYL)AMINO)-

Systematic Name

English

dasatinib [INN]

Common Name

English

Dasatinib [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Antineoplastic Enzyme Inhibitor

NCI_THESAURUS

C155700

Protein Kinase Inhibitor

NCI_THESAURUS

C1967

Established Pharmacologic Class

NDF-RT

N0000175605

Protein kinase inhibitors

WHO-ATC

L01XE06

Kinase Inhibitors

NDF-RT

N0000175076

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Code System

Code

Type

Description

RXCUI

1546019

PRIMARY

RxNorm

NDF-RT

N0000182141

PRIMARY

Cytochrome P450 3A4 Inhibitors [MoA]

MERCK INDEX

m4101

PRIMARY

Merck Index

NCI_THESAURUS

C74556

PRIMARY

EPA CompTox

DTXSID4040979

PRIMARY

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ACTIVE MOIETY


					X78UG0A0RN

DASATINIB ANHYDROUS

METABOLITE (PARENT)


					841PW2AE9X

2-(4-(6-((5-(8-CHLORO-4H-3,1-BENZOXAZIN-2-YL)THIAZOL-2-YL)AMINO)-2-METHYL-PYRIMIDIN-4-YL)PIPERAZIN-1-YL)ETHANOL

SMILES

InChI

CNS Activity

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