Related Experiment Video
Updated: Jun 5, 2025
Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Structure-Guided Discovery of Subtype Selective SIRT6 Inhibitors with a β-Carboline Skeleton for the Treatment of
Chaowei Liang1,2, Siyu Wang1,2, Dongyan Feng1,2
1Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
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.
Insights
Researchers identified a novel compound, 10d, that inhibits SIRT6, a protein promoting breast cancer drug resistance. This compound effectively suppressed tumor growth and invasion in preclinical models, offering a promising new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sirtuin 6 (SIRT6) is implicated in promoting breast cancer progression and drug resistance.
- SIRT6 enhances cancer cell survival by reinforcing DNA damage repair pathways.
Purpose of the Study:
- To identify novel SIRT6 inhibitors for breast cancer treatment.
- To investigate the therapeutic potential of SIRT6 inhibition in preclinical models.
Main Methods:
- High-throughput virtual screening and biochemical assays were employed to identify SIRT6 inhibitors.
- Structure-guided optimization led to the synthesis and evaluation of novel β-carboline derivatives.
- In vitro assays assessed compound efficacy on breast cancer cell lines (MCF-7), and in vivo studies evaluated antitumor effects.
Main Results:
- Hit 14, a novel β-carboline derivative, was identified as a potent SIRT6 inhibitor.
- Compound 10d demonstrated potent SIRT6 deacetylase inhibition (IC50 = 5.81 μM) with high subtype selectivity (>27-fold).
- 10d suppressed breast cancer cell proliferation, migration, invasion, induced apoptosis, and showed in vivo efficacy by disrupting DNA damage repair.
Conclusions:
- Compound 10d is a potent and selective SIRT6 inhibitor with demonstrated preclinical efficacy against breast cancer.
- Targeting SIRT6 represents a promising therapeutic strategy for overcoming drug resistance and treating breast cancer.
More Related Videos
Related Concept Videos
02:34Inhibition of Cdk Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...