发现新型氮杂环丁烷酰胺类强效小分子 STAT3 抑制剂。

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.

机构信息

Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii, Manoa, Honolulu, Hawaii 96813, United States.

Medicinal Chemistry Leader, Department of Chemistry, University of Hawaii, Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 9682, United States.

出版信息

J Med Chem. 2021 Jan 14;64(1):695-710. doi: 10.1021/acs.jmedchem.0c01705. Epub 2020 Dec 22.

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of ()-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 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.

我们对之前报道的脯氨酸基 STAT3 抑制剂进行了优化，得到了一系列令人兴奋的新型 ()-氮杂环丁烷-2-甲酰胺类似物，这些类似物具有亚微摩尔的效力。与对 STAT1 或 STAT5 活性的效力大于 18 μM 相比，、、和对 STAT3 具有抑制效力（IC）分别为 0.55、0.38 和 0.34 μM。进一步的修饰衍生的类似物，包括、、、和，解决了细胞膜通透性和其他物理化学问题。等温滴定量热法分析证实了与 STAT3 的高亲和力结合，分别为 880 nM () 和 960 nM ()。和抑制人乳腺癌 MDA-MB-231 或 MDA-MB-468 细胞中组成性 STAT3 磷酸化和 DNA 结合活性。此外，用、、或处理乳腺癌细胞可抑制活细胞，EC 为 0.9-1.9 μM，细胞生长和集落存活，并诱导细胞凋亡，而对正常乳腺上皮 MCF-10A 或不具有组成性激活 STAT3 的乳腺癌 MCF-7 细胞的影响相对较弱。