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Lee, Changwook
Structural Biology of Cellular Biochemistry Lab
Research Interests
  • Cell biology, structural biology, protein biochemistry, membrane biology, cancer biology

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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

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Title
Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models
Author
Kim, DarongKim, So-YeonKim, DongyoungYoon, Nam GuYun, JisuHong, Ki BumLee, ChangwookLee, Ji HoonKang, Byoung HeonKang, Soosung
Issue Date
2020-08
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
BIOORGANIC CHEMISTRY, v.101, pp.103901
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.
URI
https://scholarworks.unist.ac.kr/handle/201301/47850
URL
https://www.sciencedirect.com/science/article/pii/S0045206820300572?via%3Dihub
DOI
10.1016/j.bioorg.2020.103901
ISSN
0045-2068
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