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ID: ALA4706639
Journal: J Med Chem
Title: Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.
Authors: Brotherton-Pleiss C,Yue P,Zhu Y,Nakamura K,Chen W,Fu W,Kubota C,Chen J,Alonso-Valenteen F,Mikhael S,Medina-Kauwe L,Tius MA,Lopez-Tapia F,Turkson J
Abstract: We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of (R)-azetidine-2-carboxamide analogues that have sub-micromolar potencies. , , and have STAT3-inhibitory potencies (IC) of 0.55, 0.38, and 0.34 μM, respectively, compared to potencies greater than 18 μM against STAT1 or STAT5 activity. Further modifications derived analogues, including , , , and , that addressed cell membrane permeability and other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with K of 880 nM ( ) and 960 nM ( ). and inhibited constitutive STAT3 phosphorylation and DNA-binding activity in human breast cancer, MDA-MB-231 or MDA-MB-468 cells. Furthermore, treatment of breast cancer cells with , , , or inhibited viable cells, with an EC of 0.9-1.9 μM, cell growth, and colony survival, and induced apoptosis while having relatively weaker effects on normal breast epithelial, MCF-10A or breast cancer, MCF-7 cells that do not harbor constitutively active STAT3.
CiteXplore: 33352047