title: Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.
abstract: Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues. The first synthesized procaspase-3 activator, PAC-1, induces cancer cell apoptosis and exhibits antitumour activity in murine xenograft models. To identify more potent procaspase-3 activators, a series of compounds were designed, synthesized and evaluated for their ability of inducing cancer cell death in culture. Among these compounds, WF-208 stood out by its high cytotoxicity against procaspase-3 overexpressed HL-60 cells. Compared with PAC-1, WF-208 showed higher cytotoxicity in cancer cells and lower toxicity in normal cells. The further investigation described herein showed that WF-208 activated procaspase-3, degraded IAPs (The Inhibitors of apoptosis proteins) and leaded to caspase-3-dependent cell death in tumour cells, which possibly because of the zinc-chelating properties. WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model. In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Fangyang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008819:Mice, Nude; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000494:pharmacology
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D061945:Caspase Inhibitors; D006835:Hydrazones; D051034:Inhibitor of Apoptosis Proteins; D010879:Piperazines; D013844:Thiazoles; C000604983:WF-208; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; D015032:Zinc
keywords: PAC-1; anticancer; new derivative; procaspase-3 activator