As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle “undruggable” targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.
{"title":"Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras","authors":"Xinchen Lu, Jinmei Jin, Ye Wu, Xiaoxia Liu, Xiaohui Liang, Jiayi Lin, Qingyan Sun, Jiangjiang Qin, Weidong Zhang, Xin Luan","doi":"10.1002/med.21993","DOIUrl":"10.1002/med.21993","url":null,"abstract":"<p>As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle “undruggable” targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"812-832"},"PeriodicalIF":13.3,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138439962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yu Zheng, Yuke Li, Mao Li, Rujing Wang, Yuhong Jiang, Mengnan Zhao, Jun Lu, Rui Li, Xiaofang Li, Sanjun Shi
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the “Cytokine Storm” (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.
{"title":"COVID-19 cooling: Nanostrategies targeting cytokine storm for controlling severe and critical symptoms","authors":"Yu Zheng, Yuke Li, Mao Li, Rujing Wang, Yuhong Jiang, Mengnan Zhao, Jun Lu, Rui Li, Xiaofang Li, Sanjun Shi","doi":"10.1002/med.21997","DOIUrl":"10.1002/med.21997","url":null,"abstract":"<p>As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continue to wreak havoc worldwide, the “Cytokine Storm” (CS, also known as the inflammatory storm) or Cytokine Release Syndrome has reemerged in the public consciousness. CS is a significant contributor to the deterioration of infected individuals. Therefore, CS control is of great significance for the treatment of critically ill patients and the reduction of mortality rates. With the occurrence of variants, concerns regarding the efficacy of vaccines and antiviral drugs with a broad spectrum have grown. We should make an effort to modernize treatment strategies to address the challenges posed by mutations. Thus, in addition to the requirement for additional clinical data to monitor the long-term effects of vaccines and broad-spectrum antiviral drugs, we can use CS as an entry point and therapeutic target to alleviate the severity of the disease in patients. To effectively combat the mutation, new technologies for neutralizing or controlling CS must be developed. In recent years, nanotechnology has been widely applied in the biomedical field, opening up a plethora of opportunities for CS. Here, we put forward the view of cytokine storm as a therapeutic target can be used to treat critically ill patients by expounding the relationship between coronavirus disease 2019 (COVID-19) and CS and the mechanisms associated with CS. We pay special attention to the representative strategies of nanomaterials in current neutral and CS research, as well as their potential chemical design and principles. We hope that the nanostrategies described in this review provide attractive treatment options for severe and critical COVID-19 caused by CS.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"738-811"},"PeriodicalIF":13.3,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138289886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qineng Gong, Haojie Wang, Mi Zhou, Lu Zhou, Renxiao Wang, Yan Li
The B-cell lymphoma-2 (BCL-2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL-2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small-molecules have been designed to modulate the protein–protein interactions between anti- and proapoptotic BCL-2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL-2 homology 3 (BH3) mimetics to target antiapoptotic BCL-2 proteins, thereby competitively releasing proapoptotic BCL-2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL-2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL-2-associated X protein (BAX) or BCL-2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL-2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.
{"title":"B-cell lymphoma-2 family proteins in the crosshairs: Small molecule inhibitors and activators for cancer therapy","authors":"Qineng Gong, Haojie Wang, Mi Zhou, Lu Zhou, Renxiao Wang, Yan Li","doi":"10.1002/med.21999","DOIUrl":"10.1002/med.21999","url":null,"abstract":"<p>The B-cell lymphoma-2 (BCL-2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL-2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small-molecules have been designed to modulate the protein–protein interactions between anti- and proapoptotic BCL-2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL-2 homology 3 (BH3) mimetics to target antiapoptotic BCL-2 proteins, thereby competitively releasing proapoptotic BCL-2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL-2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL-2-associated X protein (BAX) or BCL-2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL-2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"707-737"},"PeriodicalIF":13.3,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Naga Rajiv Lakkaniga, Zhengyu Wang, Yao Xiao, Anupreet Kharbanda, Li Lan, Hong-yu Li
Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.
{"title":"Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy","authors":"Naga Rajiv Lakkaniga, Zhengyu Wang, Yao Xiao, Anupreet Kharbanda, Li Lan, Hong-yu Li","doi":"10.1002/med.21994","DOIUrl":"10.1002/med.21994","url":null,"abstract":"<p>Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"686-706"},"PeriodicalIF":13.3,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xuewu Liang, Hairu Ren, Fengyang Han, Renwen Liang, Jiayan Zhao, Hong Liu
Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin–proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets.
{"title":"The new direction of drug development: Degradation of undruggable targets through targeting chimera technology","authors":"Xuewu Liang, Hairu Ren, Fengyang Han, Renwen Liang, Jiayan Zhao, Hong Liu","doi":"10.1002/med.21992","DOIUrl":"10.1002/med.21992","url":null,"abstract":"<p>Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin–proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"632-685"},"PeriodicalIF":13.3,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138175067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiangyi Kong, Jiarui Song, Peng Gao, Ran Gao, Lin Zhang, Yi Fang, Yipeng Wang, Jidong Gao, Jing Wang
Breast cancer (BC) constitutes one of the most pervasive malignancies affecting the female population. Despite progressive improvements in diagnostic and therapeutic technologies, leading to an increased detection of early stage BCs, locally advanced breast cancer (LABC) persists as a significant clinical challenge. Owing to its poor overall survival (OS) rate, elevated recurrence rate, and high potential for distant metastasis, LABC prominently impacts the comprehensive efficacy of BC treatments. Radiotherapy, encompassing preoperative, intraoperative, and postoperative modalities, is acknowledged as an effective strategy for mitigating BC metastasis and enhancing survival rates among patients. Nevertheless, the domain of preoperative neoadjuvant radiotherapy (NART) remains conspicuously underexplored in clinical studies. Available research suggests that NART can induce tumor volume reduction, provoke fibrotic changes in tumor and adjacent normal tissues, thereby mitigating intraoperative cancer propagation and enhancing the quality of life for LABC patients. This manuscript seeks to provide a review of contemporary research pertaining to LABC and its preoperative radiotherapy.
{"title":"Revolutionizing the battle against locally advanced breast cancer: A comprehensive insight into neoadjuvant radiotherapy","authors":"Xiangyi Kong, Jiarui Song, Peng Gao, Ran Gao, Lin Zhang, Yi Fang, Yipeng Wang, Jidong Gao, Jing Wang","doi":"10.1002/med.21998","DOIUrl":"10.1002/med.21998","url":null,"abstract":"<p>Breast cancer (BC) constitutes one of the most pervasive malignancies affecting the female population. Despite progressive improvements in diagnostic and therapeutic technologies, leading to an increased detection of early stage BCs, locally advanced breast cancer (LABC) persists as a significant clinical challenge. Owing to its poor overall survival (OS) rate, elevated recurrence rate, and high potential for distant metastasis, LABC prominently impacts the comprehensive efficacy of BC treatments. Radiotherapy, encompassing preoperative, intraoperative, and postoperative modalities, is acknowledged as an effective strategy for mitigating BC metastasis and enhancing survival rates among patients. Nevertheless, the domain of preoperative neoadjuvant radiotherapy (NART) remains conspicuously underexplored in clinical studies. Available research suggests that NART can induce tumor volume reduction, provoke fibrotic changes in tumor and adjacent normal tissues, thereby mitigating intraoperative cancer propagation and enhancing the quality of life for LABC patients. This manuscript seeks to provide a review of contemporary research pertaining to LABC and its preoperative radiotherapy.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"606-631"},"PeriodicalIF":13.3,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72012759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adithi Rao, Shabir A. Bhat, Tomohiro Shibata, Jorge F. Giani, Florian Rader, Kenneth E. Bernstein, Zakir Khan
The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
{"title":"Diverse biological functions of the renin-angiotensin system","authors":"Adithi Rao, Shabir A. Bhat, Tomohiro Shibata, Jorge F. Giani, Florian Rader, Kenneth E. Bernstein, Zakir Khan","doi":"10.1002/med.21996","DOIUrl":"10.1002/med.21996","url":null,"abstract":"<p>The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"587-605"},"PeriodicalIF":13.3,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72012758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kang Wang, Yuecan Zhang, Guangji Wang, Haiping Hao, Hong Wang
Nonalcoholic fatty liver disease, also called metabolic dysfunction-associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction-associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR-based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR-based therapy for NASH/MASH, hoping to support a successful bench-to-clinic transition.
{"title":"FXR agonists for MASH therapy: Lessons and perspectives from obeticholic acid","authors":"Kang Wang, Yuecan Zhang, Guangji Wang, Haiping Hao, Hong Wang","doi":"10.1002/med.21991","DOIUrl":"10.1002/med.21991","url":null,"abstract":"<p>Nonalcoholic fatty liver disease, also called metabolic dysfunction-associated steatotic liver disease, is the most common liver disease worldwide and has no approved pharmacotherapy. Due to its beneficial effects on metabolic regulation, inflammation suppression, cell death prevention, and fibrogenesis inhibition, farnesoid X receptor (FXR) is widely accepted as a promising therapeutic target for nonalcoholic steatosis (NASH) or called metabolic dysfunction-associated steatohepatitis (MASH). Many FXR agonists have been developed for NASH/MASH therapy. Obeticholic acid (OCA) is the pioneering frontrunner FXR agonist and the first demonstrating success in clinical trials. Unfortunately, OCA did not receive regulatory approval as a NASH pharmacotherapy because its moderate benefits did not outweigh its safety risks, which may cast a shadow over FXR-based drug development for NASH/MASH. This review summarizes the milestones in the development of OCA for NASH/MASH and discuss its limitations, including moderate hepatoprotection and the undesirable side effects of dyslipidemia, pruritus, cholelithiasis, and liver toxicity risk, in depth. More importantly, we provide perspectives on FXR-based therapy for NASH/MASH, hoping to support a successful bench-to-clinic transition.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"44 2","pages":"568-586"},"PeriodicalIF":13.3,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The cover image is based on the Review Article Profiling of small-molecule necroptosis inhibitors based on the subpockets of kinase–ligand interactions by Lijuan Xu et al., https://doi.org/10.1002/med.21968.