Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy

• Published in: Bioorganic & medicinal chemistry letters Vol. 49; pp. 128286 - 128293
• Main Authors: Zhang, Mingming, Wei, Wei, Peng, Chengjun, Ma, Xiaodong, He, Xiao, Zhang, Heng, Zhou, Mingkang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2021; Elsevier
• Subjects: Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug resistance; HDAC; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; mTOR; MTOR Inhibitors - chemical synthesis; MTOR Inhibitors - metabolism; MTOR Inhibitors - pharmacology; Pharmacology & Pharmacy; Pharmacophore-merging strategy; Physical Sciences; Polypharmacological; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - metabolism; Pyrazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - metabolism; Pyrimidines - pharmacology; Science & Technology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; mTOR; Drug resistance; Pharmacophore-merging strategy; Polypharmacological; HDAC; TARGET; HISTONE DEACETYLASE INHIBITOR; IN-VITRO; POLYPHARMACOLOGY; DESIGN; ANTITUMOR-ACTIVITY; PHASE-I

[Display omitted] •Structurally novel mTOR/HDAC bi-functional inhibitors featuring pyrazolopyrimidine core were discovered.•Compound 50 exhibited remarkably potent inhibitory activity against mTOR and HDAC1.•Compound 50 exerted dramatically enhanced anti-proliferative activity against MV4-11 cell li...