1. Academic Validation
  2. Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2

  • Biochem Pharmacol. 2016 Apr 1;105:55-65. doi: 10.1016/j.bcp.2016.01.020.
Masato Ogura 1 Haruhisa Kikuchi 2 Toshiyuki Suzuki 1 Junko Yamaki 1 Miwako K Homma 1 Yoshiteru Oshima 2 Yoshimi Homma 3
Affiliations

Affiliations

  • 1 Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.
  • 2 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8678, Japan.
  • 3 Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. Electronic address: [email protected].
Abstract

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.

Keywords

Cytokine; Dermatitis; Immune response; Immunosuppressant; PQA-18 (PubChem CID: 73602831); Ppc-1 (PubChem CID: 46910769); Small molecule.

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