The Potent and Selective Oral STAT6 Degrader, KT-621, Affects Gene Transcripts in Human Keratinocytes as Effectively as Dupilumab, and Blocks Th2 Inflammation in Atopic Dermatitis and Asthma Mouse Models
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Keywords
targeted STAT6 degrader, oral therapy, preclinical, Th2 inflammation, atopic dermatitis mouse model, asthma mouse model, STAT6
Abstract
STAT6 is an essential transcription factor in the IL-4/IL-13 signaling pathways and the central driver of Th2 inflammation in allergic/atopic diseases. Multiple gain of function mutations of STAT6 have been identified to cause severe atopic/allergic diseases in humans. Dupilumab, an injectable monoclonal antibody that blocks IL-4/IL-13 signaling, is an approved therapy for multiple atopic/allergic diseases therefore targeting STAT6 in these diseases is supported by both human genetics and dupilumab’s clinical activity. STAT6 functions through protein-protein and protein-DNA interactions. It has been challenging to selectively and potently inhibit STAT6 with traditional small molecule inhibitors. However, STAT6 is well suited for a novel targeted protein degradation approach, where a simple binding event is sufficient to drive degradation of the protein and fully block its functions.
References
2. Takeda et al. Essential role of STAT6 in IL-4 signaling. Nature 1996; 380: 627-630
3. Kaplan et al. STAT6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity. 1996; 3: 313-319
3. Junttila. Tuning the cytokine responses: An update on Interleukin (IL)-4 and IL-13 receptor complexes. Front. Immunol. 2018; 9
4. Kolkhir et al., Type 2 chronic inflammatory diseases: Targets, therapies and unmet needs. Nature Reviews. Drug Discovery. 2023 August.
5. Kolkhir et al., Type 2 chronic inflammatory diseases: Targets, therapies and unmet needs. Nature Reviews. Drug Discovery. 2023 August.
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