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

Dong Lin Yang, Ya Jun Zhang, Jie Lei, Shi Qiang Li, Liu Jun He, Dian Yong Tang, Chuan Xu, Ling Tian Zhang, Jingyuan Wen, Hui Kuan Lin, Hong yu Li, Zhong Zhu Chen, Zhi Gang Xu

Producción científica: Articlerevisión exhaustiva

9 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Número de artículo114565
PublicaciónEuropean Journal of Medicinal Chemistry
Volumen240
DOI
EstadoPublished - oct 5 2022
Publicado de forma externa

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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