2. Academic Validation
  3. Pentagalloylglucose disrupts the PALB2-BRCA2 interaction and potentiates tumor sensitivity to PARP inhibitor and radiotherapy

Pentagalloylglucose disrupts the PALB2-BRCA2 interaction and potentiates tumor sensitivity to PARP inhibitor and radiotherapy

  • Cancer Lett. 2022 Oct 10;546:215851. doi: 10.1016/j.canlet.2022.215851.
Jie Zeng 1,  Jichang Han 2,  Zhaorui Liu 3,  Meng Yu 4,  Hao Li 5,  Jianzhong Yu 6
Affiliations

Affiliations

  • 1 Department of Breast and Thyroid Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, China.
  • 2 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. Electronic address: hanjichang@ucas.ac.cn.
  • 3 Department of Gastrointestinal Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China.
  • 4 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 5 Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, 201102, China. Electronic address: li_hao@fudan.edu.cn.
  • 6 Department of Neurosurgery, Children's Hospital of Fudan University, Shanghai, 201102, China. Electronic address: yu_jianzhong@fudan.edu.cn.
PMID: 35926819 DOI: 10.1016/j.canlet.2022.215851
Abstract

DNA damage repair plays a vital role in maintaining the genomic integrity of cells and has been exploited therapeutically in the treatment of Cancer. We have previously demonstrated that the upregulation of CXorf67 in posterior fossa type A ependymoma sensitizes tumor cells to PARP inhibitors by suppressing the PALB2-BRCA2 protein-protein interaction (PPI). Here, we performed structure-based virtual screening of ∼2 million small molecular entities followed by NanoBiT-based screening, and determined that pentagalloylglucose (PGG) disrupts the PALB2-BRCA2 PPI. Structure-based molecular docking and in vitro binding affinity assays revealed that PGG occupies a well-defined binding groove in the tips of the fourth and fifth blades of the PALB2 WD40 domain. PGG reduces BRCA2 recruitment to DNA damage sites and inhibits the formation of RAD51 foci, suppressing homologous recombination repair. PGG also inhibits proliferation and survival in several Cancer cell lines, including breast Cancer and medulloblastoma cells, and suppresses the in vivo growth of tumor xenografts. Thus, PGG is a specific inhibitor of the PALB2-BRCA2 PPI, which has potential value in Cancer treatment to sensitize tumors to PARP inhibitors and radiotherapy.

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