PTX80, a novel compound targeting the autophagy receptor p62/SQSTM1 for treatment of cancer

Chem Biol Drug Des. 2022 Nov;100(5):623-638. doi: 10.1111/cbdd.14046. Epub 2022 Sep 4.

Abstract

Cancer cells are dependent on protein quality-control mechanisms, including protein chaperones, the ubiquitin-proteasome system, and autophagy. The p62 receptor is a classical, ubiquitously expressed receptor, involved in many signal transduction pathways. Upregulation and/or reduced degradation of p62 have been implicated in tumor formation and resistance to therapy. PTX80 is a first-in-class novel inhibitor of protein degradation, developed by Pi Therapeutics for the treatment of cancer. PTX80 binds to p62, inducing a decrease in soluble p62 and formation of insoluble p62 aggregates, and failure of polyubiquitinated proteins to colocalize with p62. PTX80 induces proteotoxic stress and activation of unfolded protein response, which, in turn, leads to apoptosis. Targeting p62, which is a major protein degradation hub, may serve as a novel and beneficial strategy for the treatment of cancer.

Keywords: animal model of cancer; cell surface receptor drug target; in vitro model of cancer; receptors; xenograft model.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Autophagy
  • Humans
  • Neoplasms* / drug therapy
  • Proteasome Endopeptidase Complex*
  • Sequestosome-1 Protein / metabolism
  • Ubiquitin

Substances

  • Adaptor Proteins, Signal Transducing
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • Proteasome Endopeptidase Complex