dasatinib

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Ligands
dasatinib

GtoPdb Ligand ID: 5678

Synonyms: BMS 345825 | BMS 354825 | BMS 35482513 | Sprycel®

dasatinib is an approved drug (FDA & EMA (2006))

Compound class: Synthetic organic

Comment: Dasatinib is a Type-1 kinase inhibitor and was first approved by the FDA in 2006.
A combination of dasatinib and quercetin has been investigated in animal models for senolytic activity [8,13,16]. Senolytic agents are intended to reduce the abundance of senescent cells as a mechanism to treat age-related diseases, reduce frailty and extend healthy lifespan [2,5-6,15].

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: dasatinib

dasatinib is commercially available from our sponsors

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	9
Hydrogen bond donors	3
Rotatable bonds	8
Topological polar surface area	134.75
Molecular weight	487.16
XLogP	1.99
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	OCCN1CCN(CC1)c1cc(nc(n1)C)Nc1ncc(s1)C(=O)Nc1c(C)cccc1Cl
Isomeric SMILES	OCCN1CCN(CC1)c1cc(nc(n1)C)Nc1ncc(s1)C(=O)Nc1c(C)cccc1Cl
InChI	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)
InChI Key	ZBNZXTGUTAYRHI-UHFFFAOYSA-N

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Summary of Clinical Use
Tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML), including pediatric patients in the US as of November 2017 [4]. A Phase 2 clinical trial (NCT01467986) assessing dasatinib as a component of a multimodal molecular therapy to treat relapsed or refractory high-risk neuroblastoma is currently ongoing (Oct 2014).

Summary of Clinical Use

Tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML), including pediatric patients in the US as of November 2017 [4]. A Phase 2 clinical trial (NCT01467986) assessing dasatinib as a component of a multimodal molecular therapy to treat relapsed or refractory high-risk neuroblastoma is currently ongoing (Oct 2014).

Mechanism Of Action and Pharmacodynamic Effects
Dasatinib inhibits growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines that overexpress the kinase BCR-ABL. Dasatinib also inhibits the following kinases at nanomolar concentrations: SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In vitro, dasatinib is active against leukaemic cell lines expressing variants of imatinib-sensitive and resistant disease and research shows that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression.

Mechanism Of Action and Pharmacodynamic Effects

Dasatinib inhibits growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines that overexpress the kinase BCR-ABL. Dasatinib also inhibits the following kinases at nanomolar concentrations: SRC family kinases (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In vitro, dasatinib is active against leukaemic cell lines expressing variants of imatinib-sensitive and resistant disease and research shows that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression.

Pharmacokinetics
Absorption/Distribution
Oral dose of dasatinib reaches peak circulatory concentration after 0.5-3h. Protein binding is 96% and for the active metabolite, 93%.
Biotransformation/Metabolism
Extensively metabolized by CYP3A4 to an active metabolite, which is equipotent to dasatinib but also by flavin-containing monooxygenase-3 and uridine diphosphate-glucuronosyltransferase enzymes.
Elimination
Elimination is primarily via the feces (85%). Only 4% of dasatinib and its metabolites are excreted via the kidney.
Population pharmacokinetics
No significant differences in the pharmacokinetics of dasatinib have been associated with age or gender. Safety and efficacy of dasatinib have not yet been studied in paediatric patients.
Organ function impairment
There are no studies in patients with impaired renal function; however, only 4% of the drug and its metabolites are excreted by the kidney. Studies in patients with varying levels of hepatic impairement suggest that dose adjustment is not necessary in these patients.

Pharmacokinetics

Absorption/Distribution

Oral dose of dasatinib reaches peak circulatory concentration after 0.5-3h. Protein binding is 96% and for the active metabolite, 93%.

Biotransformation/Metabolism

Extensively metabolized by CYP3A4 to an active metabolite, which is equipotent to dasatinib but also by flavin-containing monooxygenase-3 and uridine diphosphate-glucuronosyltransferase enzymes.

Elimination

Elimination is primarily via the feces (85%). Only 4% of dasatinib and its metabolites are excreted via the kidney.

Population pharmacokinetics

No significant differences in the pharmacokinetics of dasatinib have been associated with age or gender. Safety and efficacy of dasatinib have not yet been studied in paediatric patients.

Organ function impairment

There are no studies in patients with impaired renal function; however, only 4% of the drug and its metabolites are excreted by the kidney. Studies in patients with varying levels of hepatic impairement suggest that dose adjustment is not necessary in these patients.