2. Academic Validation
  3. Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer

Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer

  • Eur J Med Chem. 2022 Oct 5;240:114565. doi: 10.1016/j.ejmech.2022.114565.
Dong-Lin Yang 1,  Ya-Jun Zhang 1,  Jie Lei 1,  Shi-Qiang Li 1,  Liu-Jun He 1,  Dian-Yong Tang 1,  Chuan Xu 2,  Ling-Tian Zhang 3,  Jingyuan Wen 4,  Hui-Kuan Lin 5,  Hong-Yu Li 6,  Zhong-Zhu Chen 7,  Zhi-Gang Xu 8
Affiliations

Affiliations

  • 1 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China.
  • 2 Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610047, China.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 4 School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
  • 5 Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina, 27157, USA.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. Electronic address: [email protected].
  • 7 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China. Electronic address: [email protected].
  • 8 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China. Electronic address: [email protected].
PMID: 35797901 DOI: 10.1016/j.ejmech.2022.114565
Abstract

Triple-negative breast Cancer (TNBC) with the absence of Estrogen Receptor (ER), Progesterone Receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast Cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231 and MDA-MB-468) cell lines with IC50 values of 8.3 μM, and 6.0 μM, respectively, which are comparable to the potency of 5-FU and Cisplatin, the first line therapies for TNBC. Extensive investigation of mechanisms of action indicated that 7h inhibits autophagic flux and sequential accumulation of p62, leading to DNA damage and disrepair in TNBC cells. Importantly, nuclear p62 accumulation induced by compound 7h results in the inhibition of RNF168-mediated chromatin ubiquitination and the degradation of HR-related proteins in regulating the DNA damage response (DDR) process. In in vivo studies, compound 7h completely suppressed tumor growth in the MDA-MB-231 xenograft model at a dose of 15 mg/kg/q.d. Our findings indicate that compound 7h is an autophagic flux inhibitor and induced the degradation of HR-related proteins. Compound 7h could be potentially developed as an anti-cancer therapeutics for TNBC.

Keywords

Antitumor activity; Autophagy; Benzimidazole-imidazole; DNA repair; Triple-negative breast cancer (TNBC).

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