7C04

Crystal structure of human Trap1 with DN203492

7C04 の概要

• エントリーDOI: 10.2210/pdb7c04/pdb
• 分子名称: Heat shock protein 75 kDa, mitochondrial, 4-chloranyl-1-[[2-methoxy-4-(trifluoromethyl)phenyl]methyl]pyrazolo[3,4-d]pyrimidin-6-amine (3 entities in total)
• 機能のキーワード: trap1, selectivity, mitochondria, hsp90, anticancer, drug, chaperone
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26137.58

構造登録者

Kim, D.,Kim, D.,Kim, S.Y.,Lee, J.H.,Kang, B.H.,Kang, S.,Lee, C. (登録日: 2020-04-30, 公開日: 2020-07-08, 最終更新日: 2023-11-29)

主引用文献

Kim, D.,Kim, S.Y.,Kim, D.,Yoon, N.G.,Yun, J.,Hong, K.B.,Lee, C.,Lee, J.H.,Kang, B.H.,Kang, S.
Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models.
Bioorg.Chem., 101:103901-103901, 2020

PubMed Abstract: TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.

PubMed: 32590225
DOI: 10.1016/j.bioorg.2020.103901

実験手法

X-RAY DIFFRACTION (1.7 Å)