Recently, a new and powerful technology, called “proteolysis targeting chimeras” (PROTAC), has been highlighted in the drug discovery area. Treatment of PROTAC molecule, which contains a ligand for the targeted protein, a ligand for E3 ubiquitin ligase binding, and a linker for connection of two ligands, successfully induced targeted protein degradation, thereby inhibiting cancer growth in in vivo animal model study. Anaplastic lymphoma kinase (ALK) gene fused to various partner genes are observed in 3–7% of non-small cell lung cancer (NSCLC) in humans. The constitutively activated ALK fusions play an essential role in cancer growth and survival. In this study we aimed to identify novel ALK target degraders (TDs) by applying PROTAC technology.
LDK-378 (ceritinib) as an ALK ligand and VHL or CRBN as an E3 ubiquitin ligase were selected. Hydroxyproline analogs (HP-7) and pomalidomide were used for VHL and CRBN E3 ligase ligands, respectively. All TDs were evaluated in enzymatic- and cell-based assays. ALK degradation by TDs were confirmed by western blotting in SU-DHL-1 cell lines. In vivo antitumor activities were evaluated in xenograft mouse model with H3122 cell lines.
A series of TDs were synthesized with various linkers. The TDs showed anti-ALK activities in both enzymatic and cell-based assays. The TDs exhibited ALK degradation through ubiquitination-proteasome process in cells. Finally, the TDs could inhibit tumor growth in xenograft study with H3122 cells.
These results suggest that the ALK-TDs, inducing ALK degradation, represents a promising strategy for the treatment of ALK-driven NSCLC.
Legal entity responsible for the study
Jong Yeon Hwang
Korea Research Institute of Chemical Technology
All authors have declared no conflicts of interest.