Pub Date : 2025-03-03DOI: 10.1038/s41573-025-01139-y
Javier Sánchez Lorente, Aleksandr V. Sokolov, Gavin Ferguson, Helgi B. Schiöth, Alexander S. Hauser, David E. Gloriam
G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target–disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.
{"title":"GPCR drug discovery: new agents, targets and indications","authors":"Javier Sánchez Lorente, Aleksandr V. Sokolov, Gavin Ferguson, Helgi B. Schiöth, Alexander S. Hauser, David E. Gloriam","doi":"10.1038/s41573-025-01139-y","DOIUrl":"https://doi.org/10.1038/s41573-025-01139-y","url":null,"abstract":"<p>G protein-coupled receptors (GPCRs) form one of the largest drug target families, reflecting their involvement in numerous pathophysiological processes. In this Review, we analyse drug discovery trends for the GPCR superfamily, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials. We find that there are 516 approved drugs targeting GPCRs, making up 36% of all approved drugs. These drugs act on 121 GPCR targets, one-third of all non-sensory GPCRs. Furthermore, 337 agents targeting 133 GPCRs, including 30 novel targets, are being investigated in clinical trials. Notably, 165 of these agents are approved drugs being tested for additional indications and novel agents are increasingly allosteric modulators and biologics. Remarkably, diabetes and obesity drugs targeting GPCRs had sales of nearly US $30 billion in 2023 and the numbers of clinical trials for GPCR modulators in the metabolic diseases, oncology and immunology areas are increasing strongly. Finally, we highlight the potential of untapped target–disease associations and pathway-biased signalling. Overall, this Review provides an up-to-date reference for the drugged and potentially druggable GPCRome to inform future GPCR drug discovery and development.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-28DOI: 10.1038/d41573-025-00037-7
Halda Therapeutics has started a clinical trial of its first-in-modality RIPTAC drug HLD-0915 in prostate cancer, to see if bifunctional drugs can provide tissue-specific activity.
{"title":"Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic","authors":"","doi":"10.1038/d41573-025-00037-7","DOIUrl":"https://doi.org/10.1038/d41573-025-00037-7","url":null,"abstract":"Halda Therapeutics has started a clinical trial of its first-in-modality RIPTAC drug HLD-0915 in prostate cancer, to see if bifunctional drugs can provide tissue-specific activity.","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-27DOI: 10.1038/d41573-025-00036-8
Discover the world’s best science and medicine | Nature.com
{"title":"Clinical development success rates for durable cell and gene therapies","authors":"","doi":"10.1038/d41573-025-00036-8","DOIUrl":"https://doi.org/10.1038/d41573-025-00036-8","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-26DOI: 10.1038/d41573-025-00040-y
Discover the world’s best science and medicine | Nature.com
{"title":"Genetics opens new route to degrader discovery","authors":"","doi":"10.1038/d41573-025-00040-y","DOIUrl":"https://doi.org/10.1038/d41573-025-00040-y","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"129 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1038/d41573-025-00033-x
Discover the world’s best science and medicine | Nature.com
{"title":"Oral STING agonist inhibits tumour growth","authors":"","doi":"10.1038/d41573-025-00033-x","DOIUrl":"https://doi.org/10.1038/d41573-025-00033-x","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1038/d41573-025-00035-9
Discover the world’s best science and medicine | Nature.com
{"title":"Reversing lysosomal dysfunction to treat PAH","authors":"","doi":"10.1038/d41573-025-00035-9","DOIUrl":"https://doi.org/10.1038/d41573-025-00035-9","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1038/d41573-025-00032-y
Discover the world’s best science and medicine | Nature.com
{"title":"Adrenomedullin triggers insulin resistance","authors":"","doi":"10.1038/d41573-025-00032-y","DOIUrl":"https://doi.org/10.1038/d41573-025-00032-y","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-24DOI: 10.1038/d41573-025-00034-w
Discover the world’s best science and medicine | Nature.com
{"title":"A platform for personalized ASO therapeutics","authors":"","doi":"10.1038/d41573-025-00034-w","DOIUrl":"https://doi.org/10.1038/d41573-025-00034-w","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"209 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1038/s41573-025-01143-2
Jonathan R. Whitfield, Laura Soucek
MYC is among the most infamous oncogenes in cancer. A notable feature that distinguishes it from other common oncogenes is that its deregulation is not usually due to direct mutation, but instead to its relentless activation by other oncogenic lesions. These signalling pathways funnel through MYC to execute the transcriptional programmes that eventually lead to the uncontrolled proliferation of cancer cells. Indeed, deregulated MYC activity may be linked to most — if not all — human cancers. Despite this unquestionable role of MYC in tumour development and maintenance, no MYC inhibitor has yet been approved for clinical use. The main reason is that MYC has long fallen into the category of ‘undruggable’ or ‘difficult-to-drug’ targets, mainly because of its intrinsically disordered structure, which is not amenable to traditional drug development strategies. However, in recent years, attempts to develop MYC inhibitors have multiplied, and the first clinical trials have been testing their efficacy in patients. We are finally reaching the point at which its inhibition seems clinically viable. This Review provides an overview of the various strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.
{"title":"MYC in cancer: from undruggable target to clinical trials","authors":"Jonathan R. Whitfield, Laura Soucek","doi":"10.1038/s41573-025-01143-2","DOIUrl":"https://doi.org/10.1038/s41573-025-01143-2","url":null,"abstract":"<p><i>MYC</i> is among the most infamous oncogenes in cancer. A notable feature that distinguishes it from other common oncogenes is that its deregulation is not usually due to direct mutation, but instead to its relentless activation by other oncogenic lesions. These signalling pathways funnel through MYC to execute the transcriptional programmes that eventually lead to the uncontrolled proliferation of cancer cells. Indeed, deregulated MYC activity may be linked to most — if not all — human cancers. Despite this unquestionable role of MYC in tumour development and maintenance, no MYC inhibitor has yet been approved for clinical use. The main reason is that MYC has long fallen into the category of ‘undruggable’ or ‘difficult-to-drug’ targets, mainly because of its intrinsically disordered structure, which is not amenable to traditional drug development strategies. However, in recent years, attempts to develop MYC inhibitors have multiplied, and the first clinical trials have been testing their efficacy in patients. We are finally reaching the point at which its inhibition seems clinically viable. This Review provides an overview of the various strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.</p>","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-19DOI: 10.1038/d41573-025-00031-z
Discover the world’s best science and medicine | Nature.com
{"title":"Androgen membrane receptor modulates muscle strength","authors":"","doi":"10.1038/d41573-025-00031-z","DOIUrl":"https://doi.org/10.1038/d41573-025-00031-z","url":null,"abstract":"Discover the world’s best science and medicine | Nature.com","PeriodicalId":18847,"journal":{"name":"Nature Reviews Drug Discovery","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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