dasatinib has been researched along with Triple-Negative-Breast-Neoplasms* in 2 studies
2 other study(ies) available for dasatinib and Triple-Negative-Breast-Neoplasms
| Article | Year |
|---|---|
From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer.
Herein we report the sophisticated process of structural optimization toward a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an). 13an is a multikinase inhibitor, which potently inhibited Src (IC Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Zebrafish | 2016 |
Design, Synthesis, and Structure-Activity Relationship Studies of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as a New Class of Src Inhibitors with Potent Activities in Models of Triple Negative Breast Cancer.
A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 μM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues. Topics: Acetylene; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cell Cycle; Cell Line, Tumor; Cell Movement; Drug Design; Drug Screening Assays, Antitumor; Heterografts; Humans; Male; Mice, SCID; Neoplasm Transplantation; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; src-Family Kinases; Structure-Activity Relationship; Triple Negative Breast Neoplasms | 2015 |