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

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. 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 K_D of 880 nM (7g) and 960 nM (9k). 7g and 9k</

SUBMITTER: Brotherton-Pleiss C 

PROVIDER: S-EPMC7816766 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature