title: Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors.
abstract: Functional versatility and elevated expression in cancers have promoted p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug targets. In this study, a series of novel 1-phenanthryl-tetrahydroisoquinoline analogues have been designed and synthesized as a novel class of small-molecule PAK4 inhibitors to fit into the cavity of PAK4. All of the target compounds were evaluated for their in vitro PAK4 inhibitory activities and antiproliferative activities. Lead optimization identified all the derivatives with more potency than the lead compound, especially compound 21a. Moreover, compound 21a significantly induced the cell cycle in the G1/S phase, and inhibited migration and invasion of MCF-7 cells via the regulation of the PAK4-LIMK1-cofilin signaling pathway. A molecular modeling study showed possible novel binding modes between 21a and PAK4 and provided a structural basis for further structure-guided design of PAK4 inhibitors.
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China. mscheng@263.net dongmeiz-67@163.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Song
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Chenzhou
authors.initials: C
authors.lastname: Hao
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Bingyu
authors.initials: B
authors.lastname: Guo
authors.forename: Tongchao
authors.initials: T
authors.lastname: Liu
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Lin
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhao
authors.forename: Maosheng
authors.initials: M
authors.lastname: Cheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D016086:Lentivirus / Q000378:metabolism; D061986:MCF-7 Cells; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D009665:Noscapine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D044182:Benzylisoquinolines; D007202:Indicators and Reagents; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; D044005:Tetrahydroisoquinolines; C013024:hydrastine; D009665:Noscapine; D054462:p21-Activated Kinases