title: Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2.
abstract: Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Duan
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Cao
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Saitoh
authors.forename: Nae
authors.initials: N
authors.lastname: Saito
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakaoka
authors.forename: Yao
authors.initials: Y
authors.lastname: Du
authors.forename: Atsushi
authors.initials: A
authors.lastname: Suenaga
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Kukimoto-Niino
authors.forename: Kei
authors.initials: K
authors.lastname: Miyano
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Gotoh
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohda
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C574221:4-(3'-(2'-chlorophenyl)-2'-propen-1'-ylidene)-1-phenyl-3,5-pyrazolidinedione; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D011720:Pyrazoles; D054852:Small Molecule Libraries; D020744:rac GTP-Binding Proteins