Abstract
The A2A adenosine receptor(A2AAR)has attracted attention as an emerging immunotherapeutic tar-get with several antagonists being evaluated in clinical trials.However,A2AAR antagonists show lim-ited efficacy as monotherapies.Herein,we communicate our design and synthesis of a novel series of A2AAR/histone deacetylase(HDAC)bifunctional inhibitors,based on the core structure of the A2AAR antag-onist PBF-509 The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine core.The binding affinity for A2AAR and inhibitory activity against HDACs of all the new compounds were tested.A number of compounds exhibited nanomolar or subnanomo-lar activity against both targets and some showed equally potent antiproliferative activity against MC38,CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in vitro.The binding poses of compound 5a in both A2AAR and HDAC1 were predicted by molecular docking stud-ies.Collectively,these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A2AAR/HDAC dual-acting compounds as novel antitumor agents.
基金项目
Lingang Laboratory(LG-QS-202205-03)
ShanghaiTech University and the Shanghai Municipal Government()
NETL
NSTL
维普
万方数据