PROTAC therapy as a new targeted therapy for lung cancer

Abstract

Despite recent advances in molecular therapeutics, lung cancer is still a leading cause of cancer deaths. Currently, limited targeted therapy options and acquired drug resistance present significant barriers in the treatment of patients with lung cancer. New strategies in drug development, including those that take advantage of the intracellular ubiquitin-proteasome system to induce targeted protein degradation, have the potential to advance the field of personalized medicine for patients with lung cancer. Specifically, small molecule proteolysis targeting chimeras (PROTACs), consisting of two ligands connected by a linker that bind to a target protein and an E3 ubiquitin ligase, have been developed against many cancer targets, providing promising opportunities for advanced lung cancer. In this review, we focus on the rationale for PROTAC therapy as a new targeted therapy and the current status of PROTAC development in lung cancer.

Keywords: PROTACs; argeted protein degradation; lung cancer; proteolysis targeting chimeras; targeted therapy.

Graphical abstract

Figure 1

Schematic diagram of the PROTAC technology. A typical PROTAC molecule consists of two ligands, one binding to a protein of interest (POI) and the other recruiting an E3 ligase, which are held together via a chemical linker. The PROTAC molecules induce proximity between the POI and an E3 through the formation of ternary complexes, leading to poly-ubiquitin chain formation on the POI and ultimately proteasomal-mediated POI degradation. The figure was created with BioRender.