Small molecule tyrosine kinase inhibitors for the treatment of intestinal inflammation

Maninder Sidhu, Carmen Alonso Cotoner, Bayasi Guleng, Seiji Arihiro, Sunyoung Chang, Kenneth W. Duncan, Alfred M. Ajami, Mydoanh Chau, Hans Christian Reinecker

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: We developed a series of dendritic cell autoimmune modulators (DCAMs) based on small molecule Flt3 receptor tyrosine kinase inhibitors (TKIs) for the inhibition of intestinal inflammation and oral delivery. Methods: DCAMs were administered orally during and after induction of dextran sodium sulfate (DSS)-induced colitis. Dendritic cell recruitment and inflammatory responses were determined in the mucosal immune system during acute intestinal inflammatory responses and mucosal recovery. Bone marrow-derived macrophages were utilized to define the mechanisms by which DCAMs can modify responses to microbial signals. Results: Oral doses of DCAMs prevented severe weight loss and mucosal inflammation associated with DSS colitis in mice. The presence of DCAMs increased the number of CD11c +PDCA1 + dendritic cells, induced interleukin (IL)-10 expression, and reduced inflammatory cytokine expression in the mucosal immune system. Surprisingly, DCAMs regulated innate immune responses in macrophages resulting in the inhibition of tumor necrosis factor alpha (TNF-α) production and the induction of IL-10 expression during Toll-like receptor-mediated signaling. Conclusions: We identified two new imidazoacridinone derivatives that protect mice from severe colitis and promote mucosal recovery by enhancing protective cytokine production while inhibiting proinflammatory stimuli during microbial recognition. These compounds are promising candidates for further development into potent orally available drugs for the prevention of colitis and promotion of mucosal recovery.

Original languageEnglish (US)
Pages (from-to)2416-2426
Number of pages11
JournalInflammatory bowel diseases
Volume17
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Crohn's disease
  • Flt3 receptor tyrosine kinase inhibitors
  • IL-10
  • TNF-α
  • dendritic cells
  • inflammatory bowel diseases
  • mucosal recovery
  • novel treatment
  • ulcerative colitis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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