Zhou, DonghuiSpringer, Maya Z.Xu, DavidLiu, DegangHudmon, AndyMacleod, Kay F.Meroueh, Samy O.2017-05-312017-05-312017-06Zhou, D., Springer, M. Z., Xu, D., Liu, D., Hudmon, A., Macleod, K. F., & Meroueh, S. O. (2017). Small Molecules Inhibit STAT3 Activation, Autophagy, and Cancer Cell Anchorage-Independent Growth. Bioorganic & Medicinal Chemistry. https://doi.org/10.1016/j.bmc.2017.03.048https://hdl.handle.net/1805/12788Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound’s inhibition of cell growth led to measurements of survivin, Bcl-XL, p21WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.enPublisher Policytriple-negative breast cancerbreast tumorsKIN-281Article