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  3. Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents

Structure-activity relationship studies on O-alkylamino-tethered salicylamide derivatives with various amino acid linkers as potent anticancer agents

  • Eur J Med Chem. 2022 Apr 15;234:114229. doi: 10.1016/j.ejmech.2022.114229.
Jimin Xu 1,  Hyejin Kim 2,  Jiabin Dong 2,  Haiying Chen 1,  Junhai Xu 2,  Ruixia Ma 2,  Mingxiang Zhou 1,  Tianzhi Wang 3,  Qiang Shen 4,  Jia Zhou 5
Affiliations

Affiliations

  • 1 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States.
  • 2 Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, United States.
  • 3 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, 77555, United States.
  • 4 Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, United States. Electronic address: [email protected].
  • 5 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, 77555, United States. Electronic address: [email protected].
PMID: 35334447 DOI: 10.1016/j.ejmech.2022.114229
Abstract

In our continued SAR study efforts, a series of O-alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent Anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast Cancer (BC) and triple-negative breast Cancer (TNBC) cell lines with low micromolar IC50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC50 = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC50 > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to Apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising Anticancer drug candidate for further clinical development.

Keywords

Anticancer agents; Breast cancer; Drug discovery; JMX0293; Niclosamide derivatives; STAT3 inhibitors.

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