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Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models

Title
Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models
Authors
Kim, DarongKim, So-YeonKim, DongyoungYoon, Nam GuYun, JisuHong, Ki BumLee, ChangwookLee, Ji HoonKang, Byoung HeonKang, Soosung
Ewha Authors
강수성
SCOPUS Author ID
강수성scopus
Issue Date
2020
Journal Title
BIOORGANIC CHEMISTRY
ISSN
0045-2068JCR Link

1090-2120JCR Link
Citation
BIOORGANIC CHEMISTRY vol. 101
Keywords
TRAP1SelectivityMitochondriaHsp90AnticancerDrug
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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 mi-tochondria-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 meta-bolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies con-firmed 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 hepato-cyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.
DOI
10.1016/j.bioorg.2020.103901
Appears in Collections:
약학대학 > 약학과 > Journal papers
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