2. Academic Validation
  3. Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of Breast Cancer

Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of Breast Cancer

  • J Med Chem. 2024 Dec 26;67(24):21975-22001. doi: 10.1021/acs.jmedchem.4c01921.
Chaowei Liang 1 2,  Siyu Wang 1 2,  Dongyan Feng 1 2,  Shenglin Wang 1 2,  Chao Zheng 3 4 5,  Ying Qu 1 2,  Weirenbo Wang 1 2,  Yongzhi Ma 1 2,  Haonan Li 1 2,  Hangao Yang 1 2,  Hao Cao 6,  Huiming Hua 1 2,  Maosheng Cheng 1 7,  Dahong Li 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 3 Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario M5T 1R8, Canada.
  • 4 Department of Psychiatry, University of Toronto, Toronto, Ontario M5T-1R8, Canada.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5T-1R8, Canada.
  • 6 School of Life Science and Biopharmaceutics, and Key Laboratory of Microbial Pharmaceutics, Liaoning Province, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 7 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
PMID: 39631827 DOI: 10.1021/acs.jmedchem.4c01921
Abstract

SIRT6 promotes the progression of breast Cancer by inducing drug resistance by reinforcing DNA damage repair mechanisms. This study utilized a combination of high-throughput virtual screening and FLUOR DE LYS assays. Hit 14 which features a novel β-carboline skeleton as a potent SIRT6 Inhibitor was found. Subsequent structure-guided optimization led to the synthesis of 60 3,6,9-position modified derivatives based on the differences analysis of SIRTs family proteins. Of which, 10d inhibited the deacetylase activity of SIRT6, with an IC50 of 5.81 μM and more than 27 times subtype selectivity. Phe64, Met157, and Ser56 were identified as the key residues. Moreover, 10d suppressed breast Cancer cell proliferation, migration, invasion, and induced Apoptosis in MCF-7 cells by disrupting the DNA damage repair pathway. Additionally, 10d demonstrated a safe and effective antibreast Cancer effect in vivo, presenting a promising strategy for the treatment of breast Cancer by targeting SIRT6.

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