Structure-activity relationship studies on Bax activator SMBA1 for the treatment of ER-positive and triple-negative breast cancer

  • Eur J Med Chem. 2019 Sep 15;178:589-605. doi: 10.1016/j.ejmech.2019.06.004.
Gang Liu  1 ,  Tao Yin  2 ,  Hyejin Kim  2 ,  Chunyong Ding  1 ,  Zhuo Yu  2 ,  Hong Wang  2 ,  Haiying Chen  1 ,  Ruping Yan  2 ,  Eric A Wold  1 ,  Hao Zou  2 ,  Xi Liu  2 ,  Ye Ding  1 ,  Qiang Shen  3 ,  Jia Zhou  4
Affiliations
  • 1. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States.
  • 2. Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States.
  • 3. Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States. Electronic address: [email protected].
  • 4. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States. Electronic address: [email protected].
PMID: 31220676 DOI: 10.1016/j.ejmech.2019.06.004
Abstract

In an effort to develop novel Bax activators for breast Cancer treatment, a series of diverse analogues have been designed and synthesized based on lead compound SMBA1 through several strategies, including introducing various alkylamino side chains to have a deeper access to S184 pocket, replacing carbon atoms with nitrogen, and reducing the nitro group of 9H-fluorene scaffold. Compounds 14 (CYD-2-11) and 49 (CYD-4-61) have been identified to exhibit significantly improved antiproliferative activity compared to SMBA1, with IC50 values of 3.22 μM and 0.07 μM against triple-negative breast Cancer MDA-MB-231 and 3.81 μM and 0.06 μM against ER-positive breast Cancer MCF-7 cell lines, respectively. Mechanism of action studies of compound 49 indicated that it can activate Bax protein to induce cytochrome c release and regulate apoptotic biomarkers, leading to Cancer cell Apoptosis. Further in vivo efficacy studies of compounds 14 and 49 in nude mice bearing MDA-MB-231 tumor xenografts demonstrated that these drug candidates can significantly suppress tumor growth, indicating their therapeutic potential for the treatment of breast Cancer.

Keywords
Bax activator; Breast cancer; ER-Positive; S184; SMBA1; Therapeutics; Triple-negative.
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