5P - Targeted degradation of anaplastic lymphoma kinase by target degraducer in non-small cell lung cancer

Date 17 December 2016
Event ESMO Asia 2016 Congress
Session Poster lunch
Topics Basic Science
Lung and other Thoracic Tumours
Presenter Jong Yeon Hwang
Citation Annals of Oncology (2016) 27 (suppl_9): ix1-ix8. 10.1093/annonc/mdw573
Authors J.Y. Hwang, C. Park, D.H. Lee, C.H. Kang, C.O. Lee, J.D. Ha
  • Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, 34114 - Daejeon/KR

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

Korea Research Institute of Chemical Technology

Disclosure

All authors have declared no conflicts of interest.