dasatinib

Ligand id: 5678

Name: dasatinib

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Structure and Physico-chemical Properties

2D Structure
Calculated 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 2.22
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

No information available.
Summary of Clinical Use
Tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML). A Phase II clinical trial (NCT01467986) assessing dasitinib 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.
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.
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