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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 …