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Published on: September 12, 2019
Discovery of LT-1339-553 as a Potent RIPK1 Inhibitor for Schistosomiasis-Induced Hepatic Fibrosis
Ju-Lu Lu1, Qin-Di He2, Yi-Han Yang2
1National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Provincial Medical Key Laboratory, Jiangsu Institute of Parasitic Diseases, Wuxi214064, P.R. China.
Abstract:
Hepatic fibrosis, a key pathological driver of chronic liver disease progression, lacks effective targeted therapies. Receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic target. Herein, we developed a highly potent and selective RIPK1 inhibitor, LT-1339-553 (30), through structure-based optimization. Compound 30 exhibited potent RIPK1 inhibition (IC50 = 4.32 nM) and cellular antinecroptotic activity (EC50 = 14.43 nM). In a murine model of hepatic fibrosis, 30 significantly alleviated liver injury, inflammation, and collagen deposition. Mechanistic studies revealed that its antifibrotic effects were associated with suppression of the AKT/PI3K/NF-κB and IL-17 pathways. Furthermore, 30 demonstrated good oral bioavailability and a favorable safety profile. These results position 30 as a promising candidate for the treatment of hepatic fibrosis.
Insights
A novel drug candidate, LT-1339-553, effectively inhibits Receptor-interacting protein kinase 1 (RIPK1) and shows promise in treating liver fibrosis by reducing inflammation and injury.
Area of Science:
- Pharmacology
- Hepatology
- Drug Discovery
Background:
- Hepatic fibrosis, a critical factor in chronic liver disease, requires novel targeted treatments.
- Receptor-interacting protein kinase 1 (RIPK1) is identified as a potential therapeutic target for liver fibrosis.
- Current therapeutic options for hepatic fibrosis are limited.
Purpose of the Study:
- To develop a potent and selective RIPK1 inhibitor for hepatic fibrosis treatment.
- To evaluate the efficacy and safety of the developed inhibitor in preclinical models.
- To elucidate the molecular mechanisms underlying the antifibrotic effects.
Main Methods:
- Structure-based drug design and optimization were employed to create LT-1339-553 (compound 30).
- In vitro assays were used to determine RIPK1 inhibition and cellular antinecroptotic activity.
- A murine model of hepatic fibrosis was utilized to assess in vivo efficacy.
- Mechanistic studies involved analyzing the effects on key signaling pathways like AKT/PI3K/NF-κB and IL-17.
Main Results:
- Compound 30 demonstrated high potency in inhibiting RIPK1 (IC50 = 4.32 nM) and cellular antinecroptosis (EC50 = 14.43 nM).
- In vivo studies showed significant reduction in liver injury, inflammation, and collagen deposition in a murine fibrosis model.
- LT-1339-553 suppressed the AKT/PI3K/NF-κB and IL-17 pathways, contributing to its antifibrotic effects.
- The compound exhibited good oral bioavailability and a favorable safety profile.
Conclusions:
- LT-1339-553 is a potent and selective RIPK1 inhibitor with significant therapeutic potential for hepatic fibrosis.
- The drug candidate effectively ameliorates liver fibrosis in a preclinical model through pathway modulation.
- Compound 30 represents a promising therapeutic candidate for treating chronic liver disease progression.
