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CMD-OPT模型能够发现一种强效且具有选择性的RIPK2抑制剂，作为治疗急性肝损伤的临床前候选药物。

CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury.

作者信息

Chen Yong, Yuan Xue, Yan Wei, Zou Yurong, Wei Haoche, Wei Yuhan, Tang Minghai, Chen Yulian, Ma Ziyan, Yang Tao, Liu Kongjun, Xiong Baojian, Hu Xiuying, Yang Jianhong, Chen Lijuan

机构信息

State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.

出版信息

Acta Pharm Sin B. 2025 Jul;15(7):3708-3724. doi: 10.1016/j.apsb.2025.05.003. Epub 2025 May 13.

DOI:10.1016/j.apsb.2025.05.003
PMID:40698146
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12278411/
Abstract

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-B 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 , 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 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.

摘要

急性肝损伤（ALI）是各种肝脏疾病进展和最终表现的关键先兆和主要病因。ALI的预防和治疗仍然是一项严峻的全球挑战。鉴于ALI的治疗选择有限，探索新型靶向治疗药物变得势在必行。抑制RIPK2的潜在治疗效果得到了突出，因为它可能通过减弱MAPK途径和NF-κB信号传导带来显著益处。在此，我们提出了CMD-OPT模型，这是一种用于快速发现具有最佳特性的RIPK2抑制剂的两阶段分子优化工具。靶向ATP结合位点的化合物 在对乙酰氨基酚诱导的ALI模型中表现出优异的激酶特异性、理想的口服药代动力学和卓越的治疗效果，使其成为一个有前景的临床前候选药物。这标志着RIPK2抑制剂首次应用于ALI治疗，为临床应用开辟了一条新的治疗途径。这些结果突出了CMD-OPT模型从已知活性分子中产生先导化合物的功效，展示了其在药物发现中的巨大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/c1602dfe8554/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/dd11a7c34b40/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/2e2fc0d7092d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/b96fd0d786d2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/6ac3bb9246da/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/7f0d26616425/sc2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/1f9f5e449b63/sc3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/9a03e079118b/sc4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/62bf3b0d5780/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/9919a8df16c3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/eac766b1d132/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/38d53ad99071/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/c1602dfe8554/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/dd11a7c34b40/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/2e2fc0d7092d/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/b96fd0d786d2/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/6ac3bb9246da/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/7f0d26616425/sc2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/1f9f5e449b63/sc3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/9a03e079118b/sc4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/62bf3b0d5780/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/9919a8df16c3/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/eac766b1d132/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/38d53ad99071/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a87b/12278411/c1602dfe8554/gr7.jpg

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