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Targeting hTERT Promoter G-Quadruplex DNA Structures with Small-Molecule Ligand to Downregulate hTERT Expression for Triple-Negative Breast Cancer Therapy.
Long, Wei; Zeng, Yao-Xun; Zheng, Bo-Xin; Li, Yu-Bo; Wang, Ya-Kun; Chan, Ka-Hin; She, Meng-Ting; Lu, Yu-Jing; Cao, Chunyang; Wong, Wing-Leung.
Afiliação
  • Long W; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • Zeng YX; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • Zheng BX; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • Li YB; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
  • Wang YK; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • Chan KH; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • She MT; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
  • Lu YJ; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology Guangzhou 510006, China.
  • Cao C; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
  • Wong WL; State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR 999077, China.
J Med Chem ; 67(15): 13363-13382, 2024 Aug 08.
Article em En | MEDLINE | ID: mdl-38987863
ABSTRACT
Human telomerase reverse transcriptase (hTERT) may have noncanonical functions in transcriptional regulation and metabolic reprogramming in cancer cells, but it is a challenging target. We thus developed small-molecule ligands targeting hTERT promoter G-quadruplex DNA structures (hTERT G4) to downregulate hTERT expression. Ligand 5 showed high affinity toward hTERT G4 (Kd = 1.1 µM) and potent activity against triple-negative breast cancer cells (MDA-MB-231, IC50 = 1 µM). In cell-based assays, 5 not only exerts markedly inhibitory activity on classical telomere functions including decreased telomerase activity, shortened telomere length, and cellular senescence but also induces DNA damage, acute cellular senescence, and apoptosis. This study reveals that hTERT G4-targeting ligand may cause mitochondrial dysfunction, disrupt iron metabolism and activate ferroptosis in cancer cells. The in vivo antitumor efficacy of 5 was also evaluated in an MDA-MB-231 xenograft mouse model and approximately 78.7% tumor weight reduction was achieved. No observable toxicity against the major organs was observed.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação para Baixo / Regiões Promotoras Genéticas / Telomerase / Quadruplex G / Neoplasias de Mama Triplo Negativas / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Regulação para Baixo / Regiões Promotoras Genéticas / Telomerase / Quadruplex G / Neoplasias de Mama Triplo Negativas / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article