Open AccessDiscovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors
Author(s) -
Christine BrothertonPleiss,
Peibin Yue,
Yinsong Zhu,
Kayo Nakamura,
WeiLiang Chen,
WenZhen Fu,
Casie S Kubota,
Jasmine Chen,
Felix Alonso-Valenteen,
Simoun Mikhael,
Lali K. Medina-Kauwe,
Marcus A. Tius,
Francisco LopezTapia,
James Turkson
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01705
Subject(s) - chemistry , azetidine , stat3 , isothermal titration calorimetry , cancer cell , in vitro , small molecule , annexin , cell culture , ic50 , biochemistry , apoptosis , microbiology and biotechnology , stereochemistry , cancer , biology , genetics
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 (IC 50 ) 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 K D 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 EC 50 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.