Th17 Driven Diseases and CCR6
Activated Th17 cells isolated from chronically inflamed human tissues produce high levels of TNF-α and other cytokines. A hallmark of Th17 cells is that they express high levels of the chemokine receptor known as CCR6, which is not found on Th1 and Th2 cells. High levels of the CCR6 chemokine ligand, CCL20, have been found in psoriatic skin, in rheumatoid arthritis joint biopsies, and in asthmatic lungs.
We believe that these are potential therapeutic opportunities for a CCR6 inhibitor. We have produced several unique CCR6 inhibitor leads, which are now being optimized through medicinal chemistry approaches.
The mechanism of action for CCR6 inhibitors is different from other therapeutics targeting IL-17, because inhibition of CCR6 disrupts the recruitment of infiltrating leukocytes into the epidermis upon skin damage, thereby protecting against epidermal hyperplasia, or an abnormal increase in the number of cells on the skin. Thus, pharmacological inhibition of CCR6 with an orally bioavailable small molecule inhibitor mitigates IL-17-driven inflammation in psoriasis models, and its distinct mechanism of action suggests it may offer additional efficacy when added to current standard of care.
Recent work by others in the field has also revealed potential roles for CCR6 inhibitors in the treatment of colorectal cancer (CRC). Specifically, in a mouse CRC model, mice that are genetically deficient in CCR6, as well as wild-type mice treated with a CCR6 inhibitor develop fewer intestinal polyps.
Inhibition of Chemokine Receptors CCR1 and CCR6 as Promising Therapies for Rheumatoid Arthritis
Jaen, J.; Dairaghi, D.; Leleti, M.; Powers, J.; Wang, Y.; Zhang, P.; and Schall, T. Poster Presentation at Annual European Congress of Rheumatology (EULAR) October, 2013.
CCR6 Antagonist Confers Protection Against Psoriasiform-like Disease in Mice by Limiting the Infiltration of CCR6+ Leukocytes into the Epidermis
Tan JBL; Ebsworth K; Berahovich R; Leleti M; Dairaghi D; Zhang P; Powers JP; Jaen J; Walters MJ; and Schall TS; Poster presentation at International Congress of Immunology March, 2014.