CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury
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 tar...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525003090 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850095039129059328 |
|---|---|
| author | Yong Chen Xue Yuan Wei Yan Yurong Zou Haoche Wei Yuhan Wei Minghai Tang Yulian Chen Ziyan Ma Tao Yang Kongjun Liu Baojian Xiong Xiuying Hu Jianhong Yang Lijuan Chen |
| author_facet | Yong Chen Xue Yuan Wei Yan Yurong Zou Haoche Wei Yuhan Wei Minghai Tang Yulian Chen Ziyan Ma Tao Yang Kongjun Liu Baojian Xiong Xiuying Hu Jianhong Yang Lijuan Chen |
| author_sort | Yong Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-db9950af2c1047f2a93ca804bc2c734e |
| institution | DOAJ |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-db9950af2c1047f2a93ca804bc2c734e2025-08-20T02:41:32ZengElsevierActa Pharmaceutica Sinica B2211-38352025-07-011573708372410.1016/j.apsb.2025.05.003CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injuryYong Chen0Xue Yuan1Wei Yan2Yurong Zou3Haoche Wei4Yuhan Wei5Minghai Tang6Yulian Chen7Ziyan Ma8Tao Yang9Kongjun Liu10Baojian Xiong11Xiuying Hu12Jianhong Yang13Lijuan Chen14State 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, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaState Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, ChinaInnovation 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; Corresponding authors.State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Corresponding authors.State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610212, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2211383525003090CMD-OPTAcute liver injuryRIPK2 inhibitorsAnti-inflammatoryDrug discoveryCo-crystal |
| spellingShingle | Yong Chen Xue Yuan Wei Yan Yurong Zou Haoche Wei Yuhan Wei Minghai Tang Yulian Chen Ziyan Ma Tao Yang Kongjun Liu Baojian Xiong Xiuying Hu Jianhong Yang Lijuan Chen CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury Acta Pharmaceutica Sinica B CMD-OPT Acute liver injury RIPK2 inhibitors Anti-inflammatory Drug discovery Co-crystal |
| title | CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| title_full | CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| title_fullStr | CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| title_full_unstemmed | CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| title_short | CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| title_sort | cmd opt model enables the discovery of a potent and selective ripk2 inhibitor as preclinical candidate for the treatment of acute liver injury |
| topic | CMD-OPT Acute liver injury RIPK2 inhibitors Anti-inflammatory Drug discovery Co-crystal |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525003090 |
| work_keys_str_mv | AT yongchen cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT xueyuan cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT weiyan cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT yurongzou cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT haochewei cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT yuhanwei cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT minghaitang cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT yulianchen cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT ziyanma cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT taoyang cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT kongjunliu cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT baojianxiong cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT xiuyinghu cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT jianhongyang cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury AT lijuanchen cmdoptmodelenablesthediscoveryofapotentandselectiveripk2inhibitoraspreclinicalcandidateforthetreatmentofacuteliverinjury |