53901 Potent and selective oral STAT6 degraders inhibit IL-4 and IL-13 functions in human cells and block TH2 inflammation in a mouse model of atopic dermatitis

STAT6 is an undrugged essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of TH2 inflammation in allergic diseases. Multiple gain of function mutations of STAT6 were identified to cause severe allergic diseases in human. Dupilumab, an injectable monoclonal antibody that blocks IL-4/IL-13 signaling, is an approved therapy for multiple allergic diseases. STAT6 targeting is therefore supported by both human genetics and dupilumab's clinical pathway validation. STAT6 functions through protein-protein and protein-DNA interactions. For these reasons, it has been challenging to selectively and potently inhibit STAT6 with traditional small molecule inhibitors. It is, however, well suited for a targeted protein degradation approach, where a binding event is sufficient to drive degradation. We have developed highly potent STAT6 degraders that can selectively degrade and deplete STAT6 in various disease relevant human immune and tissue cells, fully block various IL-4/IL-13 functions in these cells with picomolar potencies comparable or superior to dupilumab, and do not degrade or inhibit any other STAT transcription factors. In addition, our STAT6 degraders show potent STAT6 degradation and IL-4/ IL-13 functional inhibition in human whole blood. Our STAT6 degraders are orally bioavailable in multiple preclinical species and are able to deplete STAT6 in vivo. In a MC903-induced atopic dermatitis mouse model, orally administered STAT6 degraders demonstrated excellent in vivo efficacy, blocking TH2 inflammation and reducing disease severity. STAT6 degradation is a potential novel oral approach for blocking the IL-4/IL-13 pathways in development for the treatment of atopic dermatitis and other allergic diseases.