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Potent Dual BET/HDAC Inhibitors for Efficient Treatment of Pancreatic Cancer
Author(s) -
He Shipeng,
Dong Guoqiang,
Li Yu,
Wu Shanchao,
Wang Wei,
Sheng Chunquan
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201915896
Subject(s) - bromodomain , pancreatic cancer , brd4 , vorinostat , histone deacetylase , in vivo , bet inhibitor , pharmacology , chemistry , cancer research , hdac1 , histone deacetylase inhibitor , in vitro , cancer , small molecule , combination therapy , medicine , acetylation , histone , biochemistry , biology , microbiology and biotechnology , gene
As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small‐molecule inhibitors that simultaneously target bromodomain and extra‐terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor ( 13 a ) is identified to possess excellent and balanced activities against BRD4 BD1 (IC 50 =11 n m ) and HDAC1 (IC 50 =21 n m ). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)‐JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer.