dasatinib   Click here for help

GtoPdb Ligand ID: 5678

Synonyms: BMS 345825 | BMS 354825 | BMS 35482513 | Sprycel®
Approved drug PDB Ligand Immunopharmacology Ligand
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.
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2D Structure
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Physico-chemical Properties
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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
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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)
No information available.
Summary of Clinical Use Click here for help
Tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML), including pediatric patients in the US as of November 2017 [3]. 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 Click here for help
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 Click here for help
Oral dose of dasatinib reaches peak circulatory concentration after 0.5-3h. Protein binding is 96% and for the active metabolite, 93%.
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 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.
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