글로벌 연구동향
분자영상 및 방사화학
- 2021년 09월호
[ACS Med Chem Lett.] Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity TRAP1 선택적 억제제의 설계 및 합성이화여대 / 양수재, 윤남구, 김동영, 강수성*
- 출처
- ACS Med Chem Lett.
- 등재일
- 2021 Jun 16
- 저널이슈번호
- 12(7):1173-1180. doi: 10.1021/acsmedchemlett.1c00213.
- 내용
Abstract
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is overexpressed in the mitochondria of various cancer cells, reprograms cellular metabolism to enable cancer cells to adapt to harsh tumor environments. As inactivation of TRAP1 induces massive apoptosis in cancer cells in vitro and in vivo, the development of TRAP1-selective inhibitors has become an attractive approach. A series of purine-8-one and pyrrolo[2,3-d]pyrimidine derivatives was developed based on TRAP1 structure and identified to be highly selective in vitro for TRAP1 over the paralogous enzymes, Hsp90α and Grp94. The TRAP1-selective inhibition strategy via utilization of the Asn171 residue of the ATP-lid was investigated using X-ray crystallography and molecular dynamics simulation studies. Among various synthesized potent TRAP1 inhibitors, 5f possessed a 65-fold selectivity over Hsp90α and a 13-fold selectivity over Grp94. Additionally, 6f had a half-maximal inhibitory concentration (IC50) of 63.5 nM for TRAP1, with a 78-fold and 30-fold selectivity over Hsp90α and Grp94, respectively.Affiliations
Sujae Yang 1 , Nam Gu Yoon 2 , Dongyoung Kim 2 , Eunsun Park 1 , So-Yeon Kim 2 , Ji Hoon Lee 3 , Changwook Lee 2 , Byoung Heon Kang 2 , Soosung Kang 1
1 College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
2 Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
3 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Republic of Korea.
- 덧글달기
- 이전글 [Biomaterials.] Targeting the tumor microenvironment with amphiphilic near-infrared cyanine nanoparticles for potentiated photothermal immunotherapy
- 다음글 [J Immunother Cancer.] Escherichia coli adhesin protein-conjugated thermal responsive hybrid nanoparticles for photothermal and immunotherapy against cancer and its metastasis
편집위원
Tumor necrosis factor receptor-associated protein 1(TRAP1)은 암세포의 종양 환경 적응을 돕기 때문에, TRAP1의 비활성화를 이용하여 암세포를 자멸하게 할 수 있다. 이 논문은 TRAP1 구조 기반의 여러 TRAP1 억제제 개발에 대한 연구로, 특히 5f 및 6f 구조의 경우 TRAP1에 대하여 Hsp90α 및 Grp94에 비해 수십배 높은 in vitro 선택성을 보여주었다.
덧글달기닫기2021-09-02 13:30:25
등록