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

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

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: qshen@mdanderson.org.
  • 4 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States. Electronic address: jizhou@utmb.edu.
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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