Pub Date : 2024-11-27DOI: 10.1038/s41573-024-01104-1
Lieselotte Vande Walle, Mohamed Lamkanfi
{"title":"Author Correction: Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets","authors":"Lieselotte Vande Walle, Mohamed Lamkanfi","doi":"10.1038/s41573-024-01104-1","DOIUrl":"10.1038/s41573-024-01104-1","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"72-72"},"PeriodicalIF":122.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41573-024-01104-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-27DOI: 10.1038/d41573-024-00192-3
Sarah Crunkhorn
{"title":"Expanding the ligandable proteome","authors":"Sarah Crunkhorn","doi":"10.1038/d41573-024-00192-3","DOIUrl":"10.1038/d41573-024-00192-3","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"17-17"},"PeriodicalIF":122.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718290","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 : 2024-11-26DOI: 10.1038/s41573-024-01103-2
Dennis S. W. Lee, Olga L. Rojas, Jennifer L. Gommerman
{"title":"Author Correction: B cell depletion therapies in autoimmune disease: advances and mechanistic insights","authors":"Dennis S. W. Lee, Olga L. Rojas, Jennifer L. Gommerman","doi":"10.1038/s41573-024-01103-2","DOIUrl":"10.1038/s41573-024-01103-2","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"72-72"},"PeriodicalIF":122.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41573-024-01103-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1038/d41573-024-00188-z
Asher Mullard
{"title":"FDA approves second TTR stabilizer for cardiac amyloidosis","authors":"Asher Mullard","doi":"10.1038/d41573-024-00188-z","DOIUrl":"10.1038/d41573-024-00188-z","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"6-6"},"PeriodicalIF":122.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712879","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 : 2024-11-15DOI: 10.1038/s41573-024-01074-4
Domhnall McHugh, Imanol Durán, Jesús Gil
Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities. Recent progress in understanding senescence has spurred interest in the development of approaches that target senescent cells. This Review assesses the current status of senotherapies, such as senolytics and senomorphics, how these approaches can be combined with cancer therapies, and the challenges and opportunities in moving senotherapies to clinical practice.
{"title":"Senescence as a therapeutic target in cancer and age-related diseases","authors":"Domhnall McHugh, Imanol Durán, Jesús Gil","doi":"10.1038/s41573-024-01074-4","DOIUrl":"10.1038/s41573-024-01074-4","url":null,"abstract":"Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities. Recent progress in understanding senescence has spurred interest in the development of approaches that target senescent cells. This Review assesses the current status of senotherapies, such as senolytics and senomorphics, how these approaches can be combined with cancer therapies, and the challenges and opportunities in moving senotherapies to clinical practice.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"57-71"},"PeriodicalIF":122.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637120","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 : 2024-11-12DOI: 10.1038/s41573-024-01060-w
Yvette Drew, Frank T Zenke, Nicola J Curtin
The DNA damage response (DDR) is a network of proteins that coordinate DNA repair and cell-cycle checkpoints to prevent damage being transmitted to daughter cells. DDR defects lead to genomic instability, which enables tumour development, but they also create vulnerabilities that can be used for cancer therapy. Historically, this vulnerability has been taken advantage of using DNA-damaging cytotoxic drugs and radiotherapy, which are more toxic to tumour cells than to normal tissues. However, the discovery of the unique sensitivity of tumours defective in the homologous recombination DNA repair pathway to PARP inhibition led to the approval of six PARP inhibitors worldwide and to a focus on making use of DDR defects through the development of other DDR-targeting drugs. Here, we analyse the lessons learnt from PARP inhibitor development and how these may be applied to new targets to maximize success. We explore why, despite so much research, no other DDR inhibitor class has been approved, and only a handful have advanced to later-stage clinical trials. We discuss why more reliable predictive biomarkers are needed, explore study design from past and current trials, and suggest alternative models for monotherapy and combination studies. Targeting multiple DDR pathways simultaneously and potential combinations with anti-angiogenic agents or immune checkpoint inhibitors are also discussed. Defects in the DNA damage response have been utilized therapeutically for cancer for a decade. This Review analyses the lessons learnt from the development of PARP inhibitors and how these may be applied to new targets to maximize success. Targeting multiple DNA damage response pathways simultaneously and combinations with other therapies are also discussed.
DNA 损伤应答（DDR）是一个蛋白质网络，它协调 DNA 修复和细胞周期检查点，防止损伤传递给子细胞。DDR 缺陷会导致基因组不稳定，使肿瘤得以发展，但同时也会产生可用于癌症治疗的漏洞。一直以来，人们都是利用这种弱点，使用对 DNA 有破坏作用的细胞毒性药物和放射疗法，因为它们对肿瘤细胞的毒性比对正常组织的毒性更大。然而，同源重组DNA修复途径缺陷的肿瘤对PARP抑制具有独特的敏感性，这一发现促使全球批准了六种PARP抑制剂，并促使人们通过开发其他DDR靶向药物来重点利用DDR缺陷。在此，我们分析了从 PARP 抑制剂开发中汲取的经验教训，以及如何将这些经验教训应用于新靶点以取得最大成功。我们探讨了为什么尽管进行了如此多的研究，但仍没有其他 DDR 抑制剂类药物获得批准，只有少数几种药物进入了后期临床试验阶段。我们讨论了为什么需要更可靠的预测性生物标志物，探讨了过去和当前试验的研究设计，并提出了单药治疗和联合研究的替代模式。我们还讨论了同时靶向多种 DDR 通路以及与抗血管生成药物或免疫检查点抑制剂的潜在组合。
{"title":"DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications","authors":"Yvette Drew, Frank T Zenke, Nicola J Curtin","doi":"10.1038/s41573-024-01060-w","DOIUrl":"10.1038/s41573-024-01060-w","url":null,"abstract":"The DNA damage response (DDR) is a network of proteins that coordinate DNA repair and cell-cycle checkpoints to prevent damage being transmitted to daughter cells. DDR defects lead to genomic instability, which enables tumour development, but they also create vulnerabilities that can be used for cancer therapy. Historically, this vulnerability has been taken advantage of using DNA-damaging cytotoxic drugs and radiotherapy, which are more toxic to tumour cells than to normal tissues. However, the discovery of the unique sensitivity of tumours defective in the homologous recombination DNA repair pathway to PARP inhibition led to the approval of six PARP inhibitors worldwide and to a focus on making use of DDR defects through the development of other DDR-targeting drugs. Here, we analyse the lessons learnt from PARP inhibitor development and how these may be applied to new targets to maximize success. We explore why, despite so much research, no other DDR inhibitor class has been approved, and only a handful have advanced to later-stage clinical trials. We discuss why more reliable predictive biomarkers are needed, explore study design from past and current trials, and suggest alternative models for monotherapy and combination studies. Targeting multiple DDR pathways simultaneously and potential combinations with anti-angiogenic agents or immune checkpoint inhibitors are also discussed. Defects in the DNA damage response have been utilized therapeutically for cancer for a decade. This Review analyses the lessons learnt from the development of PARP inhibitors and how these may be applied to new targets to maximize success. Targeting multiple DNA damage response pathways simultaneously and combinations with other therapies are also discussed.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 1","pages":"19-39"},"PeriodicalIF":122.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599375","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}
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