208259-47-6Relevant articles and documents
Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors
Brotherton-Pleiss, Christine,Yue, Peibin,Zhu, Yinsong,Nakamura, Kayo,Chen, Weiliang,Fu, Wenzhen,Kubota, Casie,Chen, Jasmine,Alonso-Valenteen, Felix,Mikhael, Simoun,Medina-Kauwe, Lali,Tius, Marcus A.,Lopez-Tapia, Francisco,Turkson, James
, p. 695 - 710 (2021/01/14)
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. 5a, 5o, and 8i have STAT3-inhibitory potencies (IC50) 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 7e, 7f, 7g, and 9k, that addressed cell membrane permeability and other physicochemical issues. Isothermal titration calorimetry analysis confirmed high-affinity binding to STAT3, with KD of 880 nM (7g) and 960 nM (9k). 7g and 9k 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 7e, 7f, 7g, or 9k inhibited viable cells, with an EC50 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.
Potent α-amino-β-lactam carbamic acid ester as NAAA inhibitors. Synthesis and structure-activity relationship (SAR) studies
Nuzzi, Andrea,Fiasella, Annalisa,Ortega, Jose Antonio,Pagliuca, Chiara,Ponzano, Stefano,Pizzirani, Daniela,Bertozzi, Sine Mandrup,Ottonello, Giuliana,Tarozzo, Glauco,Reggiani, Angelo,Bandiera, Tiziano,Bertozzi, Fabio,Piomelli, Daniele
supporting information, p. 138 - 159 (2016/02/18)
4-Cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate (3b) is a potent, selective and systemically active inhibitor of intracellular NAAA activity, which produces profound anti-inflammatory effects in animal models. In the present work, we describe structure-activity relationship (SAR) studies on 3-aminoazetidin-2-one derivatives, which have led to the identification of 3b, and expand these studies to elucidate the principal structural and stereochemical features needed to achieve effective NAAA inhibition. Investigations on the influence of the substitution at the β-position of the 2-oxo-3-azetidinyl ring as well as on the effect of size and shape of the carbamic acid ester side chain led to the discovery of 3ak, a novel inhibitor of human NAAA that shows an improved physicochemical and drug-like profile relative to 3b. This favourable profile, along with the structural diversity of the carbamic acid chain of 3b, identify this compound as a promising new tool to investigate the potential of NAAA inhibitors as therapeutic agents for the treatment of pain and inflammation.
STAT3 DIMERIZATION INHIBITORS
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Page/Page column 70, (2014/05/24)
The subject matter disclosed herein relates to compositions and methods of making and using the compositions. In a further aspect, the subject matter disclosed herein relates to inhibitors of STAT3 dimerization. Methods of making these compositions as wel
