Pub Date : 2025-05-20DOI: 10.1016/j.pharmthera.2025.108880
Peter Holzer
{"title":"Editorial: Pharmacological targets for the control of tissue remodelling and fibrosis","authors":"Peter Holzer","doi":"10.1016/j.pharmthera.2025.108880","DOIUrl":"10.1016/j.pharmthera.2025.108880","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108880"},"PeriodicalIF":12.0,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126143","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}
Pub Date : 2025-05-19DOI: 10.1016/j.pharmthera.2025.108879
Eimear T. O’Mahony , Christopher M. Arian , Kayenat S. Aryeh , Kai Wang , Kenneth E. Thummel , Edward J. Kelly
The application of human enteroid systems presents a significant opportunity within the drug development pipeline, highlighting considerable potential for advancements in the characterization and evaluation of new molecular entities. Derived from LGR5+ crypt-based columnar cells, enteroid systems more accurately recapitulate the microanatomy and physiological processes of the human intestinal mucosa compared to traditionally used systems. They contain the complement of major mucosal epithelial cell types, maintain the genetic identity of the donor and intestinal segment they were derived from, and exhibit biological functions and specific activities that are seen in vivo. In this review, we examine the applications of human enteroid systems in nonclinical drug development and compare findings to existing and emerging in vitro models of the small intestine. Specifically, we explore enteroid systems in the context of predicting oral drug disposition, focusing on apparent permeability, intestinal first-pass metabolism, and drug interactions, as well as their utility in assessing drug-induced gastrointestinal toxicity and screening therapeutic efficacy against enteric diseases. Additionally, we highlight aspects of enteroid systems that warrant further study.
{"title":"Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy","authors":"Eimear T. O’Mahony , Christopher M. Arian , Kayenat S. Aryeh , Kai Wang , Kenneth E. Thummel , Edward J. Kelly","doi":"10.1016/j.pharmthera.2025.108879","DOIUrl":"10.1016/j.pharmthera.2025.108879","url":null,"abstract":"<div><div>The application of human enteroid systems presents a significant opportunity within the drug development pipeline, highlighting considerable potential for advancements in the characterization and evaluation of new molecular entities. Derived from LGR5<sup>+</sup> crypt-based columnar cells, enteroid systems more accurately recapitulate the microanatomy and physiological processes of the human intestinal mucosa compared to traditionally used systems. They contain the complement of major mucosal epithelial cell types, maintain the genetic identity of the donor and intestinal segment they were derived from, and exhibit biological functions and specific activities that are seen <em>in vivo</em>. In this review, we examine the applications of human enteroid systems in nonclinical drug development and compare findings to existing and emerging <em>in vitro</em> models of the small intestine. Specifically, we explore enteroid systems in the context of predicting oral drug disposition, focusing on apparent permeability, intestinal first-pass metabolism, and drug interactions, as well as their utility in assessing drug-induced gastrointestinal toxicity and screening therapeutic efficacy against enteric diseases. Additionally, we highlight aspects of enteroid systems that warrant further study.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108879"},"PeriodicalIF":12.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118466","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}
Pub Date : 2025-05-16DOI: 10.1016/j.pharmthera.2025.108877
K. Helivier Solís, M. Teresa Romero-Ávila, Rocío Alcántara-Hernández, J. Adolfo García-Sáinz
Receptor-mediated cell activation frequently results in a plethora of effects, and interestingly, not all agonists that act on a given receptor activate all of those actions to the same extent. Biased agonism refers to this fact, i.e., the possibility to activate only a part of the receptor's signaling capabilities. It is worth mentioning that Biased Signaling is an integral concept that includes the system (organisms, isolated tissues, or cells), the individual receptor studied, and the ligands. It should be remembered that the system's genetic expression profile defines the type, abundance, and cellular localization of proteins that participate in signaling. This short review will be focused on G protein receptors, but biased signaling occurs in many other receptor types.
Biased signaling can be related to the G proteins and β-arrestins available. Similarly, enzymes that catalyze receptor posttranslational modifications, such as phosphorylation, acylation, or ubiquitination, can play a role. G protein-coupled receptor signaling occurs at the plasma membrane, but it is well-established that endosomal signaling is a functional reality. Therefore, paying attention to cellular elements that participate in receptor endosomal traffic and destination (recycling to the plasma membrane/ degradation) is pertinent. There is still much to be known about these bias mechanisms, which are essential for basic knowledge of receptor drug action and for treating many pathological entities.
{"title":"The many facets of biased signaling: Mechanisms and possible therapeutic implications","authors":"K. Helivier Solís, M. Teresa Romero-Ávila, Rocío Alcántara-Hernández, J. Adolfo García-Sáinz","doi":"10.1016/j.pharmthera.2025.108877","DOIUrl":"10.1016/j.pharmthera.2025.108877","url":null,"abstract":"<div><div>Receptor-mediated cell activation frequently results in a plethora of effects, and interestingly, not all agonists that act on a given receptor activate all of those actions to the same extent. Biased agonism refers to this fact, i.e., the possibility to activate only a part of the receptor's signaling capabilities. It is worth mentioning that Biased Signaling is an integral concept that includes the system (organisms, isolated tissues, or cells), the individual receptor studied, and the ligands. It should be remembered that the system's genetic expression profile defines the type, abundance, and cellular localization of proteins that participate in signaling. This short review will be focused on G protein receptors, but biased signaling occurs in many other receptor types.</div><div>Biased signaling can be related to the G proteins and β-arrestins available. Similarly, enzymes that catalyze receptor posttranslational modifications, such as phosphorylation, acylation, or ubiquitination, can play a role. G protein-coupled receptor signaling occurs at the plasma membrane, but it is well-established that endosomal signaling is a functional reality. Therefore, paying attention to cellular elements that participate in receptor endosomal traffic and destination (recycling to the plasma membrane/ degradation) is pertinent. There is still much to be known about these bias mechanisms, which are essential for basic knowledge of receptor drug action and for treating many pathological entities.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108877"},"PeriodicalIF":12.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092365","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}
Pub Date : 2025-05-16DOI: 10.1016/j.pharmthera.2025.108878
Yang Li , Qiao Liu , Chuan-Ying Pan , Xian-Yong Lan
Free Fatty Acid Receptor 2 (FFA2), also known as GPR43, is a receptor activated by short-chain fatty acids (SCFAs) with fewer than six carbons in their aliphatic chains. This receptor is expressed in immune cells, adipose tissue, the gastrointestinal tract, and pancreatic islet cells, where it plays a crucial role in the modulation of inflammation, lipid metabolism, insulin secretion, and appetite regulation. Extensive research has been conducted to elucidate the structural attributes and physiological functions of FFA2. Furthermore, several synthetic agonists have been developed for FFA2 that can preferentially activate certain G-proteins, demonstrating potential pharmacological advantages in both in vivo and in vitro studies. Herein, we review the structure and physiological functions of FFA2 and its synthetic ligands, discussing the structural basis of FFA2's biased signaling and the potential role of biased ligands targeting this receptor in the treatment of metabolic and neurodegenerative diseases.
{"title":"The free fatty acid receptor 2 (FFA2): Mechanisms of action, biased signaling, and clinical prospects","authors":"Yang Li , Qiao Liu , Chuan-Ying Pan , Xian-Yong Lan","doi":"10.1016/j.pharmthera.2025.108878","DOIUrl":"10.1016/j.pharmthera.2025.108878","url":null,"abstract":"<div><div>Free Fatty Acid Receptor 2 (FFA2), also known as GPR43, is a receptor activated by short-chain fatty acids (SCFAs) with fewer than six carbons in their aliphatic chains. This receptor is expressed in immune cells, adipose tissue, the gastrointestinal tract, and pancreatic islet cells, where it plays a crucial role in the modulation of inflammation, lipid metabolism, insulin secretion, and appetite regulation. Extensive research has been conducted to elucidate the structural attributes and physiological functions of FFA2. Furthermore, several synthetic agonists have been developed for FFA2 that can preferentially activate certain G-proteins, demonstrating potential pharmacological advantages in both in vivo and in vitro studies. Herein, we review the structure and physiological functions of FFA2 and its synthetic ligands, discussing the structural basis of FFA2's biased signaling and the potential role of biased ligands targeting this receptor in the treatment of metabolic and neurodegenerative diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108878"},"PeriodicalIF":12.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092461","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}
Pub Date : 2025-05-14DOI: 10.1016/j.pharmthera.2025.108876
Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia
The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with in vitro physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, in vitro, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.
{"title":"Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing","authors":"Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia","doi":"10.1016/j.pharmthera.2025.108876","DOIUrl":"10.1016/j.pharmthera.2025.108876","url":null,"abstract":"<div><div>The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with <em>in vitro</em> physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, <em>in vitro</em>, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108876"},"PeriodicalIF":12.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085592","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}
Pub Date : 2025-05-06DOI: 10.1016/j.pharmthera.2025.108875
Reza Tabrizchi
Approximately 1.3 billion adults globally have hypertension, and are at higher risk of death associated with cardiovascular disease. Adjusted death rate primarily due to high blood pressure is 31.3 per 100,000. The prevalence of drug-resistant hypertension is estimated to be up to 20 % in hypertensive individuals, and is more common in those with chronic kidney disease and obstructive sleep apnea. It occurs in individuals on ≥3 antihypertensive drugs including a diuretic. The addition of spironolactone, as a fourth drug has been found at times to be effective in management of blood pressure. Other strategies include sequential nephron block (e.g., spironolactone + furosemide + amiloride), and use of drugs such as alpha2 agonists, endothelin antagonists, and nonsteroidal mineralocorticoid antagonists. Use of positive airway pressure and pharmacotherapy have been found to be of value in individuals with sleep apnea in lowering blood pressure. In contrast, baroreceptor stimulation and/or renal denervation combined with pharmacotherapy seem to offer little in a way of consistent efficacy of optimally lowering blood pressures. Remarkably, evidence in the literature strongly supports the view that life style changes including regular exercise and appropriate diet combined with pharmacotherapy can lead to positive outcomes in helping to significantly reduce blood pressure. There is also ample data in literature suggesting the non-compliance to antihypertensive medications as a significant barrier to lowering blood pressure in this group. Accordingly, education regarding pharmacotherapy, and appropriate exercise regimen, including changes to diet should underpin any strategy in the management of high blood pressure in this population.
{"title":"Management of drug-resistant hypertension as a heterogeneous disorder","authors":"Reza Tabrizchi","doi":"10.1016/j.pharmthera.2025.108875","DOIUrl":"10.1016/j.pharmthera.2025.108875","url":null,"abstract":"<div><div>Approximately 1.3 billion adults globally have hypertension, and are at higher risk of death associated with cardiovascular disease. Adjusted death rate primarily due to high blood pressure is 31.3 per 100,000. The prevalence of drug-resistant hypertension is estimated to be up to 20 % in hypertensive individuals, and is more common in those with chronic kidney disease and obstructive sleep apnea. It occurs in individuals on ≥3 antihypertensive drugs including a diuretic. The addition of spironolactone, as a fourth drug has been found at times to be effective in management of blood pressure. Other strategies include sequential nephron block (e.g., spironolactone + furosemide + amiloride), and use of drugs such as alpha<sub>2</sub> agonists, endothelin antagonists, and nonsteroidal mineralocorticoid antagonists. Use of positive airway pressure and pharmacotherapy have been found to be of value in individuals with sleep apnea in lowering blood pressure. In contrast, baroreceptor stimulation and/or renal denervation combined with pharmacotherapy seem to offer little in a way of consistent efficacy of optimally lowering blood pressures. Remarkably, evidence in the literature strongly supports the view that life style changes including regular exercise and appropriate diet combined with pharmacotherapy can lead to positive outcomes in helping to significantly reduce blood pressure. There is also ample data in literature suggesting the non-compliance to antihypertensive medications as a significant barrier to lowering blood pressure in this group. Accordingly, education regarding pharmacotherapy, and appropriate exercise regimen, including changes to diet should underpin any strategy in the management of high blood pressure in this population.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108875"},"PeriodicalIF":12.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935759","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}
Cancer is the second-largest death-causing disease after cardiovascular diseases. Effective research on cancer diagnosis and subsequent elimination plays a vital role in reducing the cancer-related death toll. Radiotherapy is one of the best strategies that could kill masses of solid tumour tissues; however, the efficacy is limited due to the bystander effect. This issue could be solved by the emergence of targeted delivery of radiometallic complexes, enabling clinicians to monitor the tumour regions and effectively destroy the tumour. Affibody® molecules are a class of synthetic peptides known as antibody mimics having the binding sites of an antibody. The specificity of affibodies is found to be greater than that of antibodies due to their small size. This review intends to highlight the recent developments in the field of affibody-targeted radiometallopharmaceuticals. These approaches could be essential for early cancer detection, tumour staging, and monitoring the response to therapy and could produce better therapeutic outcomes. In an attempt to provide ideas and inspiration for the researchers to design affibody-conjugated radiopharmaceuticals that are clinically applicable, we have provided an in-depth exploration of the various types of affibody-conjugated radiopharmaceuticals that are currently in clinical trials and various other pre-clinically tested conjugates in this article. Only a few review reports on affibody-conjugated radiometallopharmaceuticals, typically focusing on a specific molecular target or radionuclides reported. In this review, we provide a comprehensive overview of most radiometals, such as 111In, 68Ga, 64Cu, 55Co, 57Co, 44Sc, 99mTc, 89Zr, 90Y, 211At, 188Re, and 177Lu, choice of chelators, and potential cancer-associated molecular targets such HER2, EGFR or HER1, HER3, IGF-1R, PDGFRβ, VEGFR2, PD-L1, CAIX, PD-L1, neonatal Fc receptor (FcRn) and B7-H3. This approach highlights the advancements made over the past twenty years in affibody conjugates for radio imaging and therapy in oncology.
{"title":"Unlocking the power of affibody conjugated radioactive metallopharmaceuticals for targeted cancer diagnosis and therapy","authors":"Dhanashree Murugan , Harashkumar Vasanthakumari Thirumalaiswamy , Vasanth Murugesan , Janarthanan Venkatesan , Unnikrishnan Balachandran , Kalaiarasu Lakshminarayanan , Drishty Satpati , Stefan Nikolić , Loganathan Rangasamy","doi":"10.1016/j.pharmthera.2025.108863","DOIUrl":"10.1016/j.pharmthera.2025.108863","url":null,"abstract":"<div><div>Cancer is the second-largest death-causing disease after cardiovascular diseases. Effective research on cancer diagnosis and subsequent elimination plays a vital role in reducing the cancer-related death toll. Radiotherapy is one of the best strategies that could kill masses of solid tumour tissues; however, the efficacy is limited due to the bystander effect. This issue could be solved by the emergence of targeted delivery of radiometallic complexes, enabling clinicians to monitor the tumour regions and effectively destroy the tumour. Affibody® molecules are a class of synthetic peptides known as antibody mimics having the binding sites of an antibody. The specificity of affibodies is found to be greater than that of antibodies due to their small size. This review intends to highlight the recent developments in the field of affibody-targeted radiometallopharmaceuticals. These approaches could be essential for early cancer detection, tumour staging, and monitoring the response to therapy and could produce better therapeutic outcomes. In an attempt to provide ideas and inspiration for the researchers to design affibody-conjugated radiopharmaceuticals that are clinically applicable, we have provided an in-depth exploration of the various types of affibody-conjugated radiopharmaceuticals that are currently in clinical trials and various other pre-clinically tested conjugates in this article. Only a few review reports on affibody-conjugated radiometallopharmaceuticals, typically focusing on a specific molecular target or radionuclides reported. In this review, we provide a comprehensive overview of most radiometals, such as <sup>111</sup>In, <sup>68</sup>Ga, <sup>64</sup>Cu, <sup>55</sup>Co, <sup>57</sup>Co, <sup>44</sup>Sc, <sup>99m</sup>Tc, <sup>89</sup>Zr, <sup>90</sup>Y, <sup>211</sup>At, <sup>188</sup>Re, and <sup>177</sup>Lu, choice of chelators, and potential cancer-associated molecular targets such HER2, EGFR or HER1, HER3, IGF-1R, PDGFRβ, VEGFR2, PD-L1, CAIX, PD-L1, neonatal Fc receptor (FcRn) and B7-H3. This approach highlights the advancements made over the past twenty years in affibody conjugates for radio imaging and therapy in oncology.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108863"},"PeriodicalIF":12.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954530","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}
Pub Date : 2025-04-22DOI: 10.1016/j.pharmthera.2025.108865
Carlos Torrado , Nicholas W. Ashton , Alan D. D'Andrea , Timothy A. Yap
Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme involved in the DNA damage response. Upon DNA damage, USP1 stabilizes replication forks by removing monoubiquitin from PCNA and FANCD2-FANCI, thereby catalyzing critical final steps in translesion synthesis and interstrand crosslink (ICL) repair. This function is particularly crucial in BRCA1 mutant cancers, where the homologous recombination pathway is compromised, leading tumors to rely on USP1 for effective repair. USP1 is also overexpressed in BRCA1 mutant cancers, as well as other tumor types. Preclinical studies have demonstrated that knockout of USP1 is synthetically lethal in tumors with biallelic BRCA1 mutations, and this relationship is enhanced by combination with PARP inhibitors. Newly developed USP1 inhibitors have confirmed this synthetic lethality in BRCA1-deficient tumor cells. Moreover, these drugs have the potential for resensitizing platinum-resistant tumors. Currently, potent and specific USP1 inhibitors are undergoing evaluation in phase I clinical trials. RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309–101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors.
{"title":"USP1 inhibition: A journey from target discovery to clinical translation","authors":"Carlos Torrado , Nicholas W. Ashton , Alan D. D'Andrea , Timothy A. Yap","doi":"10.1016/j.pharmthera.2025.108865","DOIUrl":"10.1016/j.pharmthera.2025.108865","url":null,"abstract":"<div><div>Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme involved in the DNA damage response. Upon DNA damage, USP1 stabilizes replication forks by removing monoubiquitin from PCNA and FANCD2-FANCI, thereby catalyzing critical final steps in translesion synthesis and interstrand crosslink (ICL) repair. This function is particularly crucial in <em>BRCA1</em> mutant cancers, where the homologous recombination pathway is compromised, leading tumors to rely on USP1 for effective repair. USP1 is also overexpressed in <em>BRCA1</em> mutant cancers, as well as other tumor types. Preclinical studies have demonstrated that knockout of USP1 is synthetically lethal in tumors with biallelic BRCA1 mutations, and this relationship is enhanced by combination with PARP inhibitors. Newly developed USP1 inhibitors have confirmed this synthetic lethality in BRCA1-deficient tumor cells. Moreover, these drugs have the potential for resensitizing platinum-resistant tumors. Currently, potent and specific USP1 inhibitors are undergoing evaluation in phase I clinical trials. RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309–101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108865"},"PeriodicalIF":12.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873285","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}
Pub Date : 2025-04-22DOI: 10.1016/j.pharmthera.2025.108864
Chao Zhong , Keke Deng , Xiaoya Lang , Dan Shan , Yanfei Xie , Wen Pan , Jun Yu
Atherosclerosis and its associated cardiovascular complications remain significant global public health challenges, underscoring the urgent need for effective therapeutic strategies. Endothelial cells are critical for maintaining vascular health and homeostasis, and their dysfunction is a key contributor to the initiation and progression of atherosclerosis. Targeting endothelial dysfunction has, therefore, emerged as a promising approach for the prevention and management of atherosclerosis. Among natural products, flavonoids, a diverse class of plant-derived phenolic compounds, have garnered significant attention for their anti-atherosclerotic properties. A growing body of evidence demonstrates that flavonoids can mitigate endothelial dysfunction, highlighting their potential as endothelial dysfunction-targeted therapeutics for atherosclerosis. In this review, we summarize current knowledge on the roles of natural flavonoids in modulating various aspects of endothelial dysfunction and their therapeutic effects on atherosclerosis, focusing on the underlying molecular mechanisms. We also discuss the challenges and future prospects of translating natural flavonoids into clinical applications for cardiovascular medicine. This review aims to provide critical insights to advance the development of novel endothelium-protective pharmacotherapies for atherosclerosis.
{"title":"Therapeutic potential of natural flavonoids in atherosclerosis through endothelium-protective mechanisms: An update","authors":"Chao Zhong , Keke Deng , Xiaoya Lang , Dan Shan , Yanfei Xie , Wen Pan , Jun Yu","doi":"10.1016/j.pharmthera.2025.108864","DOIUrl":"10.1016/j.pharmthera.2025.108864","url":null,"abstract":"<div><div>Atherosclerosis and its associated cardiovascular complications remain significant global public health challenges, underscoring the urgent need for effective therapeutic strategies. Endothelial cells are critical for maintaining vascular health and homeostasis, and their dysfunction is a key contributor to the initiation and progression of atherosclerosis. Targeting endothelial dysfunction has, therefore, emerged as a promising approach for the prevention and management of atherosclerosis. Among natural products, flavonoids, a diverse class of plant-derived phenolic compounds, have garnered significant attention for their anti-atherosclerotic properties. A growing body of evidence demonstrates that flavonoids can mitigate endothelial dysfunction, highlighting their potential as endothelial dysfunction-targeted therapeutics for atherosclerosis. In this review, we summarize current knowledge on the roles of natural flavonoids in modulating various aspects of endothelial dysfunction and their therapeutic effects on atherosclerosis, focusing on the underlying molecular mechanisms. We also discuss the challenges and future prospects of translating natural flavonoids into clinical applications for cardiovascular medicine. This review aims to provide critical insights to advance the development of novel endothelium-protective pharmacotherapies for atherosclerosis.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108864"},"PeriodicalIF":12.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879029","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}
Pub Date : 2025-04-21DOI: 10.1016/j.pharmthera.2025.108862
Josef Biber , Catharina Gandor , Elvir Becirovic , Stylianos Michalakis
Gene therapy is an innovative medical approach that offers new treatment options for congenital and acquired diseases by transferring, correcting, inactivating or regulating genes to supplement, replace or modify a gene function. The approval of voretigene neparvovec (Luxturna), a gene therapy for RPE65-associated retinopathy, has marked a milestone for the field of retinal gene therapy, but has also helped to accelerate the development of gene therapies for genetic diseases affecting other organs. Voretigene neparvovec is a vector based on adeno-associated virus (AAV) that delivers a functional copy of RPE65 to supplement the missing function of this gene. The AAV-based gene delivery has proven to be versatile and safe for the transfer of genetic material to retinal cells. However, challenges remain in treating additional inherited as well as acquired retinopathies with this technology. Despite the high level of activity in this field, no other AAV gene therapy for retinal diseases has been approved since voretigene neparvovec. Ongoing research focuses on overcoming the current restraints through innovative strategies like AAV capsid engineering, dual-AAV vector systems, or CRISPR/Cas-mediated genome editing. Additionally, AAV gene therapy is being explored for the treatment of complex acquired diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) by targeting molecules involved in the pathobiology of the degenerative processes. This review outlines the current state of retinal gene therapy, highlighting ongoing challenges and future directions.
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