|STAT6||Inflammatory Disease||Lead Optimization|
|STAT3||Inflammatory Disease||Lead Optimization|
Recludix is pursuing a distinct approach to modulate the activity of the JAK/STAT family of pathways by targeting the downstream STAT proteins through inhibition of their SH2 domains. Targeting individual STAT proteins with highly selective inhibitors is expected to provide a more focused biological response than is observed with many JAK family kinase inhibitors. This may result in fewer side effects and the ability to more profoundly inhibit a specific pathway, even in cancer, at well tolerated doses.
STAT3 in Cancer
More than 70% of human cancers exhibit abnormally elevated STAT3 activity and levels of phosphorylated STAT3 have been shown to correlate with poor clinical outcomes in several cancers.
Recurring, activating hotspot mutations are found in STAT3 in multiple leukemias and lymphomas. These include large granular lymphocytic leukemia, about 50% of which harbor STAT3 mutations, with STAT3 activated in virtually all patients regardless of STAT3 mutation status, and diffuse large B-cell lymphoma, with a STAT3 mutation frequency of approximately 5%.
STAT3 mutations in these diseases are largely mutually exclusive with other known oncogenic mutations, strongly suggesting that STAT3 mutations are oncogenic drivers. Tumors with these mutations therefore are likely to be sensitive to STAT3 inhibition.
STAT3 also plays a pivotal role in tumor-infiltrating immune cells that comprise the tumor microenvironment (TME). Hyperactivation of STAT3 in the TME results in immunosuppression by inhibiting both innate and adaptive immune responses, including through the accumulation and enrichment of immunosuppressive Treg cells and the polarization of M2-macrophages, which contribute to immune evasion. Additionally, STAT3 activation is a driver for increased expression of immune checkpoint molecules (such as PD-L1, PD-L2 and CTLA-4) in these cells. Inhibition of STAT3 in this context has the potential to improve the anti-cancer immune response.
STAT3 in Inflammatory Disease
Both IL-6 and IL-23, cytokines important for Th17 cell differentiation and function, signal through STAT3. Th17 cells are implicated in the pathogenesis of a number of inflammatory diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and others.
Inhibition of STAT3 with oral small molecule drugs therefore represents an attractive alternative to biologics and to JAK family kinase inhibitors to interfere with Th17 cell activity and treat Th17-driven inflammatory and autoimmune disease.
STAT6 in Cancer
Recurring, activating hotspot mutations are found in STAT6 across B-cell lymphomas, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and follicular lymphoma. Approximately 5 to 30% of patients with these diseases harbor STAT6 mutations.
STAT6 mutations in B-cell lymphomas are largely mutually exclusive with other known oncogenic mutations, strongly suggesting that STAT6 mutations are oncogenic drivers. Tumors with these mutations therefore are likely to be sensitive to STAT6 inhibition.
STAT6 in Inflammatory Disease
IL-4 and IL-13, cytokines important for Th2 cell differentiation and function, signal through STAT6. Th2 cells are implicated in the pathogenesis of atopic dermatitis, asthma and allergies, and inhibitors of IL-4 and IL-13 signaling are highly effective in these Th2-driven diseases.
Inhibition of STAT6 with oral small molecule drugs represents an attractive alternative to biologics targeting IL-4 and IL-13 and to JAK family kinase inhibitors to interfere with Th2 cell activity and treat Th2-driven inflammatory and autoimmune disease.