Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

• Published in: Biochemical pharmacology 2016-04, Vol.105, p.55-65
• Main Authors: Ogura, Masato, Kikuchi, Haruhisa, Suzuki, Toshiyuki, Yamaki, Junko, Homma, Miwako K., Oshima, Yoshiteru, Homma, Yoshimi
• Format: Article
• Language: English
• Subjects: Animals; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Cytokine; Dermatitis; Dermatitis - drug therapy; Dermatitis - immunology; Dermatitis - metabolism; Dose-Response Relationship, Drug; Humans; Immune response; Immunity, Cellular - drug effects; Immunity, Cellular - immunology; Immunity, Cellular - physiology; Immunosuppressant; Immunosuppressive Agents - pharmacology; Jurkat Cells; Male; Mice; Mice, Inbred C57BL; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - immunology; p21-Activated Kinases - metabolism; Prenylation - drug effects; Prenylation - immunology; Prenylation - physiology; Quinolines - chemistry; Quinolines - pharmacology; Small molecule; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Triiodobenzoic Acids - pharmacology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2016.01.020

[Display omitted] Development of new immunosuppressing agents is necessary in organ transplantation or immune diseases. Because Ppc-1 exhibits a suppressing effect on interleukin-2 (IL2) production in Jurkat cells, we synthesized and screened Ppc-1 derivatives that preserve prenylated quinolinecarboxylic acid (PQA) structure, and identified compound 18 (PQA-18) as a novel molecule with immunosuppressing effect. PQA-18 suppressed not only IL2 but also IL4, IL6, and tumor necrosis factor-α production in human peripheral lymphocytes without affecting cell viability. Two-dimensional gel electrophoresis analysis and in vitro kinase assay revealed that PQA-18 inhibits kinase activity of p21-activated kinase 2 (PAK2). Administration of PQA-18 by intraperitoneal injection suppressed the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens in mice. Treatment with the PQA-18 ointment on Nc/Nga mice, a model of human atopic dermatitis, improved skin lesions and serum IgE levels. These results suggest that PQA-18 is a unique PAK2 inhibitor with potent immunosuppressing effects in vitro and in vivo. PQA-18 may be a valuable lead for the development of novel immunosuppressants.