Introduction and Objective: Diabetic foot ulcers (DFUs) are chronic, slow-healing wounds characterized by unresolved inflammation affecting a significant proportion of patients with diabetes. Dysregulated NLRP3 inflammasome activation in diabetic wounds contributes to chronic inflammation, impeding tissue repair and promoting ulcer chronicity. NLRP3 expression is significantly upregulated in patients with DFUs compared to healthy controls.Methods: THP-1 derived macrophages and primary cells were used to evaluate compound activity in vitro. Selectivity was assessed by testing against other inflammasomes and a 44-panel safety assay. Hyperglycemia was induced in mice with STZ and a full-thickness wound created on the dorsal skin. Efficacy was assessed by wound closure rate.Results: Using our AI-based drug discovery platforms, we developed ISM5059, a peripherally restricted NLRP3 inhibitor with nanomolar inhibition potency of IL-1β (IC50 10.2 nM) and IL-18 (IC50 9.1 nM) release in THP-1-derived macrophages. ISM5059 showed similar activity in primary human monocytes and mouse bone marrow-derived macrophages. ISM5059 displays high selectivity, with no inhibitory activity on AIM2, NLRC4, NLRP1 inflammasomes, and a clean safety profile in a 44-panel screen. In vivo efficacy evaluated in an STZ-induced diabetic foot ulcer mouse model found ISM5059 accelerated wound healing in a dose-dependent fashion; at 6 mg/kg, its effect was comparable to the positive control, dapagliflozin. Combined treatment with dapagliflozin further accelerated wound closure, achieving healing rates similar to those observed in non-diabetic, healthy mice. ISM5059 exhibited favorable drug-like properties, including optimal in vitro ADMET profiles, strong in vivo exposure and clearance, and excellent oral bioavailability across multiple preclinical species.Conclusion: These findings establish ISM5059 as an effective and selective peripheral NLRP3 inhibitor with robust efficacy and a promising safety margin for potential treatment of diabetic foot ulcers.
Z. Cao: Employee; Current; Insilico Medicine. M. Zhang: Employee; Current; Insilico Medicine. X. Cai: Employee; Current; Insilico Medicine. C. Satler: Employee; Current; Insilico Medicine. D. Gennert: Employee; Current; Insilico Medicine. J. Wu: Employee; Current; Insilico Medicine. L. Qin: Employee; Current; Insilico Medicine. F. Ren: Employee; Current; Insilico Medicine. A. Zhavoronkov: Employee; Current; Insilico Medicine.
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