120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-332
Subject Chemically induced target degradation of anaplastic lymphoma kinase (ALK) by Target Degraducers (TDs) [우수포스터상], [동우화인켐㈜ 대학(원)생 선정 포스터상]
Authors Dong-Ho Lee, jae du ha1, Duck-Hyung Lee, Jong Yeon Hwang2,*
Department of Chemistry, Sogang University, Korea
1WCI, Korea Research Institute of Chemical Technology, Korea
2Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Korea
Abstract Recently, a new and powerful technology called "proteomosis targeting chimeras" (PROTAC) has been actively applied in the field of drug development. 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 discover 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 used. Hydroxyproline analogs (HP-7) and pomalidomide were used for VHL and CRBN E3 ligase ligands, respectively. All TDs synthesized in this study 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.
E-mail leedh112577@gmail.com