Dasatinib

Tyrosine kinase inhibitor; Inhibits ABL, SRC, LCK and YES

Dasatinib

Tyrosine kinase inhibitor; Inhibits ABL, SRC, LCK and YES

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Tyrosine kinase inhibitor; Inhibits ABL, SRC, LCK and YES
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Overview

Dasatinib is a potent, ATP-competitive tyrosine kinase inhibitor. It is specific for SRC/ABL kinases, for example, ABL, SRC, LCK, and YES with IC₅₀ values of < 1.0, 0.5, 0.4 and 0.5 nM, respectively, and also demonstrates activity against KIT with an IC₅₀ = 5.0 nM (Lombardo et al.; Davis et al.) Dasatinib is a second-generation inhibitor of the oncogenic tyrosine kinase BCR-ABL with 325-fold more potency than imatinib, and is also able to inhibit imatinib-resistant BCR-ABL mutants (Tokarski et al.). It also inhibits a large number of other kinases (76 of 148 kinases tested) when screened at 10 μM (Carter et al.).

CANCER RESEARCH
· Inhibits proliferation in cell lines derived from chronic myeloid leukemia (CML), prostate, breast, and colon tumors (Lombardo et al.).
· Inhibits proliferation of cells with imatinib-resistant BCR-ABL mutations (Shah et al.).
· Inhibits tumor growth and development of lymph node metastases in orthotopic nude mouse models of prostate cancer (Park et al.).
· Induces cell-cycle arrest and apoptosis and decreases growth in thyroid cancer cells (Chan et al.).
· Inhibits production of extracellular matrix proteins in dermal fibroblasts and prevents development of bleomycin-challenge-induced fibrosis in mice (Distler & Distler; Akhmetshina et al.).
Cell Type
Cancer Cells and Cell Lines, Leukemia/Lymphoma Cells
Species
Human, Mouse, Non-Human Primate, Other, Rat
Area of Interest
Cancer
CAS Number
302962-49-8
Chemical Formula
C₂₂H₂₆ClN₇O₂S
Purity
≥ 98%
Pathway
Tyrosine Kinase
Target
ABL, LCK, SRC

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Product Name
Dasatinib
Catalog #
73082, 73084
Lot #
Lot# 1000028163 or lower for 73082 | Lot# 1000027795 or lower for 73084
Language
English
Product Name
Dasatinib
Catalog #
73082, 73084
Lot #
Lot# 1000028164 or higher for 73082 | Lot# 1000027796 or higher for 73084
Language
English
Document Type
Safety Data Sheet
Product Name
Dasatinib
Catalog #
73082, 73084
Lot #
All
Language
English

Resources and Publications

Educational Materials (2)

Publications (9)

Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis. Chan CM et al. Clinical cancer research : an official journal of the American Association for Cancer Research 2012

Abstract

PURPOSE: There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. EXPERIMENTAL DESIGN: The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant. RESULTS: Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90&percnt; (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively). CONCLUSION: These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.
Comprehensive analysis of kinase inhibitor selectivity. Davis MI et al. Nature biotechnology 2011

Abstract

We tested the interaction of 72 kinase inhibitors with 442 kinases covering textgreater80&percnt; of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Park SI et al. Cancer research 2008

Abstract

Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)-mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression.