A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Medium-Throughput Detection of Hsp90/Cdc37 Protein-Protein Interaction Inhibitors Using a Split Renilla Luciferase-Based Assay
Tekijät: Farid Ahmad Siddiqui, Hanna Parkkola, Ganesh babu Manoharan, Daniel Abankwa
Kustantaja: SAGE PUBLICATIONS INC
Julkaisuvuosi: 2019
Journal: SLAS discovery
Tietokannassa oleva lehden nimi: SLAS DISCOVERY
Lehden akronyymi: SLAS DISCOV
Artikkelin numero: UNSP 2472555219884033
Vuosikerta: 25
Numero: 2
Aloitussivu: 195
Lopetussivu: 206
Sivujen määrä: 12
ISSN: 2472-5552
eISSN: 2472-5560
DOI: https://doi.org/10.1177/2472555219884033
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/44403113
The protein-folding chaperone Hsp90 enables the maturation and stability of various oncogenic signaling proteins and is thus pursued as a cancer drug target. Folding in particular of protein kinases is assisted by the co-chaperone Cdc37. Several inhibitors against the Hsp90 ATP-binding site have been developed. However, they displayed significant toxicity in clinical trials. By contrast, the natural product conglobatin A has an exceptionally low toxicity in mice. It targets the protein-protein interface (PPI) of Hsp90 and Cdc37, suggesting that interface inhibitors have an interesting drug development potential. In order to identify inhibitors of the Hsp90/Cdc37 PPI, we have established a mammalian cell lysate-based, medium-throughput amenable split Renilla luciferase assay. This assay employs N-terminal and C-terminal fragments of Renilla luciferase fused to full-length human Hsp90 and Cdc37, respectively. We expect that our assay will allow for the identification of novel Hsp90/Cdc37 interaction inhibitors. Such tool compounds will help to evaluate whether the toxicity profile of Hsp90/Cdc37 PPI inhibitors is in general more favorable than that of ATP-competitive Hsp90 inhibitors. Further development of such tool compounds may lead to new classes of Hsp90 inhibitors with applications in cancer and other diseases.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
