Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity
- 주제(키워드) TRAP1 , HSP90 , Inhibitor , Selectivity , Mitochondria , Cancer
- 주제(기타) Chemistry, Medicinal
- 설명문(일반) [Yang, Sujae; Park, Eunsun; Lee, Changwook; Kang, Soosung] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Yoon, Nam Gu; Kim, Dongyoung; Kim, So-Yeon; Kang, Byoung Heon] Ulsan Natl Inst Sci & Technol UNIST, Dept Biol Sci, Ulsan 44919, South Korea; [Lee, Ji Hoon] Daegu Gyeongbuk Med Innovat Fdn DGMIF, New Drug Dev Ctr, Daegu 41061, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000182278
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/acsmedchemlett.1c00213
초록/요약
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.
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