IL-17A blocker – a first in class opportunity in inflammatory diseases

Inhibition or blocking of IL-17A has been well validated in the clinic for improving inflammatory diseases with marketed antibody medication showing good efficacy in treating skin diseases like psoriasis as well as arthritis diseases like ankylosing spondylitis and psoriatic arthritis to name a few.

In Nuevolution’s IL-17A program, we have screened more than 40.000.000.000.000 compounds using the Chemetics® platform and identified three series of compounds with distinct chemotypes each comprising potent small molecules that directly and selectively bind the human IL17A homo-dimer protein, thereby blocking IL-17A function. The lead compounds show good properties and potent blockade of IL-17A dependent cell signalling in human skin cells (keratinocytes). Multiple IL-17A-compound x-ray (three-dimensional picture) structures have been generated showing 2 distinct mechanisms of IL-17A binding. These high-resolution pictures of the mechanism of inhibition provide invaluable support to the further lead optimization of our compounds.

Figure 1. IL-17A inhibition with a Nuevolution small molecule compound. A representative example of a Nuevolution small molecule compound (molecular weight less than 480 Dalton) binding IL-17A to prevent cytokine binding to the IL-17A receptor (panel 1) in an AlphaScreen assay. The compound inhibits IL-17A with an IC50 of 22 nM. The compound also potently represses IL-17A “disease” cell-signalling in human keratinocytes (panel 2) with an apparent IC50 of 18 nM. The distinct mechanism of binding of each Nuevolution compound series is detailed by multiple high-resolution co-crystal (3-D) structures between the Nuevolution small molecules and the IL-17A homodimer and supports our ongoing medicinal chemistry efforts (panel 3 and 4).

The program is currently in lead optimization and comprise more than 2200 synthesized and profiled compounds with more than 140 compounds showing high potency (IC50 < 100 nM), low MW (molecular weight < 550 Da) and good drug-like physicochemical properties.

Figure 2. A Nuevolution IL-17A blocker tested in an in vivo efficacy study using the collagen-induced arthritis (CIA) mouse model with therapeutic dosing. Mice show a high degree of “arthritis” clinical scoring when left untreated (red line). In contrast, an antibody specific for IL-17A dosed intraperitoneally (injection) prevents further disease progression (blue line). A Nuevolution small molecule IL-17A blocker (molecular weight less than 480 Da) dosed subcutaneously, twice daily, provides a dose-proportional effect in clinical scoring with the highest dose of 180 milligram-per-kilogram mouse (mpk) giving a reduction in clinical arthritis score equivalent to the neutralizing IL-17A antibody (dark green).

The program is currently focused on the identification of the first topical IL-17A blockers as well as compounds with systemic exposure for future next generation tablet-based IL-17A treatment options.