2. Academic Validation
  3. Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer

Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer

  • Eur J Med Chem. 2023 Nov 29:264:116009. doi: 10.1016/j.ejmech.2023.116009.
Ying Wang 1,  Aima Huang 2,  Lu Chen 1,  Fan Sun 2,  Man Zhao 1,  Ming Zhang 1,  Yubao Xie 1,  Shiyu Xu 2,  Min Li 3,  Liang Hong 4,  Guofeng Li 5,  Rui Wang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
  • 2 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 3 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: [email protected].
  • 4 Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: [email protected].
  • 5 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China; Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 38070430 DOI: 10.1016/j.ejmech.2023.116009
Abstract

Triple-negative breast Cancer (TNBC) is an extremely aggressive tumor with limited treatment options and effectiveness. Dual-target inhibitors capable of simultaneously suppressing invasion may represent a promising therapeutic approach for TNBC. In this work, we developed a series of dual BRD4/Src inhibitors by connecting JQ1 and dasatinib using various linkers and evaluated their efficacy against TNBC both in vitro and in vivo. Among these compounds, HL403 demonstrated IC50 values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. Most importantly, HL403 not only exhibited potent anti-proliferative capabilities, but also effectively suppressed the invasion of MDA-MB-231 cells in vitro. Finally, the anti-tumor efficacy of HL403 was validated in a mouse MDA-MB-231 xenograft tumor model, achieving a tumor growth inhibition rate (TGI) of 70.7 %, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0 %). Our research provides a promising and feasible new strategy for improving the treatment of TNBC.

Keywords

BRD4; Dual inhibitor; Src; TNBC.

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