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| Type |
Poster Presentation |
| Area |
의약화학 |
| Room No. |
포스터발표장 |
| Time |
4월 20일 (목요일) 11:00~12:30 |
| Code |
MEDI.P-457 |
| Subject |
Targeted degradation of anaplastic lymphoma kinase (ALK): Design and synthesis of target degraducers (TDs) |
| Authors |
이동호, 장예린1, 소민섭2, 이덕형, 하재두3, 황종연1,*
서강대학교 화학과, Korea
1한국화학연구원 의약화학연구센터, Korea
2충남대학교 화학과, Korea
3한국화학연구원 난치성질환치료제연구센터, Korea
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| 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 |
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119th General Meeting of the KCS