2. Academic Validation
  3. Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative

Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative

  • Bioorg Chem. 2020 Jun;99:103817. doi: 10.1016/j.bioorg.2020.103817.
Jian Zhang 1,  Pan Chen 2,  Peiyu Zhu 1,  Peiyuan Zheng 1,  Tao Wang 1,  Lixun Wang 1,  Changliang Xu 3,  Jinpei Zhou 4,  Huibin Zhang 5
Affiliations

Affiliations

  • 1 Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, PR China. Electronic address: [email protected].
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
  • 5 Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 32361153 DOI: 10.1016/j.bioorg.2020.103817
Abstract

Bromodomain-containing protein 4 (BRD4) plays a crucial role in the epigenetic regulation of gene transcription and some BRD4 inhibitors have been advanced to clinical trials. Nevertheless, the clinical application of BRD4 inhibitors could be limited by drug resistance. As an alternative strategy, the emerging Proteolysis Targeting Chimeras (PROTACs) technology has the potential to overcome the drug resistance of traditional small-molecule drugs. Based on PROTACs approaches, several BRD4 degraders were developed and have been proved to degrade BRD4 protein and inhibit tumor growth. Herein, we present the design, synthesis, and biological evaluation of pyrrolopyridone derivative-based BRD4 degraders. Four synthesized compounds displayed comparative potence against BRD4 BD1 with IC50 at low nanomolar concentrations. Anti-proliferative activity of 32a against BxPC3 cell line (IC50 = 0.165 μM) was improved by about 7-fold as compared to the BRD4 Inhibitor ABBV-075. Furthermore, degrader 32a potently induced the degradation of BRD4 and inhibited the expression of c-Myc in BxPC3 cell line in a time-dependent manner. The exploration of intracellular antitumor mechanism showed 32a induced cell cycle arrest and Apoptosis effectively. All the results demonstrated that compound 32a could be considered as a potential BRD4 Degrader for further investigation.

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