View : 523 Download: 0
Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity
- Title
- Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity
- Authors
- Yang, Sujae; Yoon, Nam Gu; Kim, Dongyoung; Park, Eunsun; Kim, So-Yeon; Lee, Ji Hoon; Lee, Changwook; Kang, Byoung Heon; Kang, Soosung
- Ewha Authors
- 강수성
- SCOPUS Author ID
- 강수성
- Issue Date
- 2021
- Journal Title
- ACS MEDICINAL CHEMISTRY LETTERS
- ISSN
- 1948-5875
- Citation
- ACS MEDICINAL CHEMISTRY LETTERS vol. 12, no. 7, pp. 1173 - 1180
- Keywords
- TRAP1; HSP90; Inhibitor; Selectivity; Mitochondria; Cancer
- Publisher
- AMER CHEMICAL SOC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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, Hsp90 alpha and Grp94. The TRAP I-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 TRAP I inhibitors, 5f possessed a 65-fold selectivity over Hsp90 alpha 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 Hsp90 alpha and Grp94, respectively.
- DOI
- 10.1021/acsmedchemlett.1c00213
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML