Background/Purpose: Inhibition of JAK family signaling has translated into clinically meaningful efficacy in rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases. However, small molecule JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated hematologic homeostasis (anemia, thrombocytopenia).

Oral selective STAT3 inhibitors represent an opportunity to target inflammatory cytokines, including IL-6 and IL-17, that are validated mediators in rheumatologic diseases. The STAT3 SH2 domain mediates both binding to the cytokine receptor and transcriptional activity, and therefore is an attractive therapeutic target.

Methods: Recludix has developed an innovative and proprietary SH2 domain platform that has enabled the discovery of a new class of small molecule inhibitors of these previously undruggable protein domains.

Results: REX-7117 is the first orally available, reversible, SH2 domain-targeting STAT3 inhibitor. REX-7117 demonstrated low nanomolar potency in biochemical and primary human cellular assays, high selectivity across the SH2 family, including other STAT proteins, and inhibited IL-6 driven inflammation. Unlike JAK1/2 inhibitors, REX-7117 did not impair innate interferon-dependent anti-viral immunity, or growth factor signaling critical for hematologic homeostasis. In dogs and mice, REX-7117 achieved deep, durable, and selective STAT3 inhibition, decreased inflammatory biomarkers such as CRP, and achieved statistically significant efficacy in a rodent model of inflammatory arthritis.

Conclusion: Selective STAT3 inhibition brings the promise of combining the efficacy of clinically validated biologics with the convenience of oral administration, while potentially avoiding known safety concerns observed with the broader activity of JAK/TYK2 inhibitors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rex-7117-is-a-highly-potent-and-selective-oral-stat3-inhibitor-that-demonstrated-potential-efficacy-and-safety-differentiation-versus-jak-tyk2-targeting-in-preclinical-models-of-inflammatory-arthritis/