title: Repositioning Potential of PAK4 to Osteoclastic Bone Resorption.
abstract: Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.
authors: Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Sik-Won
authors: SW
authors: Choi
authors: Department of Pharmacy, Sunchon National University, Suncheon, South Korea.
authors: Jeong-Tae
authors: JT
authors: Yeon
authors: Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Byung Jun
authors: BJ
authors: Ryu
authors: Department of Pharmacy, Sunchon National University, Suncheon, South Korea.
authors: Kwang-Jin
authors: KJ
authors: Kim
authors: Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Seong-Hee
authors: SH
authors: Moon
authors: Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Hyuk
authors: H
authors: Lee
authors: Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk, South Korea.
authors: Myeung Su
authors: MS
authors: Lee
authors: Department of Cardiac and Thoracic Surgery, Wonkwang University, Iksan, Jeonbuk, South Korea.
authors: Sam Youn
authors: SY
authors: Lee
authors: Pharmacology Research Center, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Jin-Chul
authors: JC
authors: Heo
authors: Department of Histology, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
authors: Sang-Joon
authors: SJ
authors: Park
authors: Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors: Seong Hwan
authors: SH
authors: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000473:pathology; D001862:Bone Resorption / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D004195:Disease Models, Animal; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C550923:PF 3758309; D011720:Pyrazoles; D011758:Pyrroles; C492065:Pak4 protein, mouse; D054462:p21-Activated Kinases
keywords: DRUG REPOSITION; OSTEOCLAST; OSTEOCLAST FUSION; PAK4 INHIBITOR; PODOSOME