{"title":"新出现的RAS抑制剂：杂环和螺旋环化合物在癌症治疗中的应用。","authors":"Robert B Kargbo","doi":"10.1021/acsmedchemlett.5c00028","DOIUrl":null,"url":null,"abstract":"<p><p>Researchers have long recognized RAS mutations as one of the most challenging targets in oncology. These genetic alterations are central drivers of tumor progression in cancers such as melanoma, colorectal cancer, and pancreatic adenocarcinoma. The recent advancements described in patent applications WO 2024/243186 A2 and WO 2024/246099 A1 introduce two novel classes of inhibitors: heterocyclic compounds targeting NRAS G12D and spirocyclic derivatives directed at KRAS mutations, including G12C, G12D, and G12 V. These compounds, a fresh and innovative approach, disrupt critical RAS-dependent signaling pathways, offering a pathway to mitigate tumor growth and overcome resistance to standard therapies. This Patent Highlight explores their mechanisms, preclinical successes, and implications for future cancer treatment strategies.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"216-218"},"PeriodicalIF":3.5000,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831559/pdf/","citationCount":"0","resultStr":"{\"title\":\"Emerging RAS Inhibitors: Heterocyclic and Spirocyclic Compounds in Cancer Therapeutics.\",\"authors\":\"Robert B Kargbo\",\"doi\":\"10.1021/acsmedchemlett.5c00028\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Researchers have long recognized RAS mutations as one of the most challenging targets in oncology. These genetic alterations are central drivers of tumor progression in cancers such as melanoma, colorectal cancer, and pancreatic adenocarcinoma. The recent advancements described in patent applications WO 2024/243186 A2 and WO 2024/246099 A1 introduce two novel classes of inhibitors: heterocyclic compounds targeting NRAS G12D and spirocyclic derivatives directed at KRAS mutations, including G12C, G12D, and G12 V. These compounds, a fresh and innovative approach, disrupt critical RAS-dependent signaling pathways, offering a pathway to mitigate tumor growth and overcome resistance to standard therapies. This Patent Highlight explores their mechanisms, preclinical successes, and implications for future cancer treatment strategies.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"16 2\",\"pages\":\"216-218\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-01-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831559/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsmedchemlett.5c00028\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/13 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.5c00028","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/13 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Emerging RAS Inhibitors: Heterocyclic and Spirocyclic Compounds in Cancer Therapeutics.
Researchers have long recognized RAS mutations as one of the most challenging targets in oncology. These genetic alterations are central drivers of tumor progression in cancers such as melanoma, colorectal cancer, and pancreatic adenocarcinoma. The recent advancements described in patent applications WO 2024/243186 A2 and WO 2024/246099 A1 introduce two novel classes of inhibitors: heterocyclic compounds targeting NRAS G12D and spirocyclic derivatives directed at KRAS mutations, including G12C, G12D, and G12 V. These compounds, a fresh and innovative approach, disrupt critical RAS-dependent signaling pathways, offering a pathway to mitigate tumor growth and overcome resistance to standard therapies. This Patent Highlight explores their mechanisms, preclinical successes, and implications for future cancer treatment strategies.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
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