Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious glob...Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious global challenge.Given the limited therapeutic options for ALI,exploring novel targeted therapeutic agents becomes imperative.The potential therapeutic efficacy of inhibiting RIPK2 is highlighted,as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling.Herein,we propose a CMD-OPT model,a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties.Compound RP20,which targets the ATP binding site,demonstrated excellent kinase specificity,ideal oral pharmacokinetics,and superior therapeutic effects in a model of APAP-induced ALI,positioning RP20 as a promising preclinical candidate.This marks the first application of RIPK2 inhibitors in ALI treatment,opening a novel therapeutic pathway for clinical applications.These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules,showcasing its significant potential in drug discovery.展开更多
Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bi...Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bioavailability^(1,2,3).Inflammation driven by MAPK and NF-κB pathways exacerbates hepatocellular damage,positioning receptor-interacting serine/threonine kinase 2(RIPK2)as an attractive target to attenuate pro-inflammatory signaling and apoptosis^(4,5).Early RIPK2 inhibitors such as GSK2983559 advanced into clinical trials for inflammatory bowel disease but faltered due to safety and pharmacokinetic drawbacks6.Addressing these challenges,Chen et al.7 introduce a two-stage,transformer-based CMD-OPT model to refine scaffold design and ADME properties of lead RIPK2 inhibitors,culminating in compound RP20-a selective,orally bioavailable preclinical candidate exhibiting robust hepatoprotective effects in APAP-induced ALI models.展开更多
基金supported by the National Natural Science Foundation of China(82304282 and T2221004)the Natural Science Foundation of Sichuan,China(2024NSFSC1733)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD23020).
文摘Acute liver injury(ALI)serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders.The prevention and treatment of ALI is still a serious global challenge.Given the limited therapeutic options for ALI,exploring novel targeted therapeutic agents becomes imperative.The potential therapeutic efficacy of inhibiting RIPK2 is highlighted,as it may provide significant benefits by attenuating the MAPK pathway and NF-κB signaling.Herein,we propose a CMD-OPT model,a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties.Compound RP20,which targets the ATP binding site,demonstrated excellent kinase specificity,ideal oral pharmacokinetics,and superior therapeutic effects in a model of APAP-induced ALI,positioning RP20 as a promising preclinical candidate.This marks the first application of RIPK2 inhibitors in ALI treatment,opening a novel therapeutic pathway for clinical applications.These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules,showcasing its significant potential in drug discovery.
文摘Acetaminophen(APAP)overdose remains a leading cause of acute liver injury(ALI)worldwide,with limited therapeutic options except for N-acetylcysteine(NAC),whose efficacy is hampered by short half-life and suboptimal bioavailability^(1,2,3).Inflammation driven by MAPK and NF-κB pathways exacerbates hepatocellular damage,positioning receptor-interacting serine/threonine kinase 2(RIPK2)as an attractive target to attenuate pro-inflammatory signaling and apoptosis^(4,5).Early RIPK2 inhibitors such as GSK2983559 advanced into clinical trials for inflammatory bowel disease but faltered due to safety and pharmacokinetic drawbacks6.Addressing these challenges,Chen et al.7 introduce a two-stage,transformer-based CMD-OPT model to refine scaffold design and ADME properties of lead RIPK2 inhibitors,culminating in compound RP20-a selective,orally bioavailable preclinical candidate exhibiting robust hepatoprotective effects in APAP-induced ALI models.
