{"id":3022,"date":"2025-07-16T08:50:44","date_gmt":"2025-07-16T08:50:44","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=3022"},"modified":"2025-07-16T08:50:44","modified_gmt":"2025-07-16T08:50:44","slug":"discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\/","title":{"rendered":"Discovery of an NF-\u03baB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate"},"content":{"rendered":"<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-3023\" src=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW-300x169.jpg\" alt=\"\" width=\"950\" height=\"535\" srcset=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW-300x169.jpg 300w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW-1024x576.jpg 1024w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW-768x432.jpg 768w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW.jpg 1280w\" sizes=\"auto, (max-width: 950px) 100vw, 950px\" \/><\/p>\n<p><span style=\"font-size: 14pt;\"><strong>ABSTRACT<\/strong><\/span><\/p>\n<p>In this study, the coumarin natural product minutuminolate (MNT) was used as a starting point for the development of anti-inflammatory agents. Through structure\u2212activity relationship studies, a lead compound MD-1 was designed and synthesized, exhibiting significantly improved antiinflammatory activities. Mechanistic studies revealed that MD-1 is a degrader of the p105 subunit of NF-\u03baB. Gene knockdown experiments further showed that the Cullin-ring ligase (CRL) SCF\u03b2TrCP is involved in MD-1-induced p105 degradation. This leads to suppressed NF-\u03baB transcriptional activity, which is consistent with its potent anti-inflammatory effects. Taken together, our work challenges the longstanding notion that NF-\u03baB is undruggable, as we demonstrate that the p105 subunit of NF-\u03baB is indeed tractable with small molecules. More importantly, our study highlights that natural products are valuable starting points for the discovery and development of antiinflammatory agents with novel mechanisms of action.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>ABSTRACT In this study, the coumarin natural product minutuminolate (MNT) was used as a starting point for the development of anti-inflammatory agents. Through structure\u2212activity relationship studies, a lead compound MD-1 was designed and synthesized, exhibiting significantly improved antiinflammatory activities. Mechanistic studies revealed that MD-1 is a degrader of the p105 subunit of NF-\u03baB. Gene knockdown [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":3023,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"default","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-3022","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.6 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Discovery of an NF-\u03baB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/discovery-of-an-nf-\u03bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Discovery of an NF-\u03baB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"ABSTRACT In this study, the coumarin natural product minutuminolate (MNT) was used as a starting point for the development of anti-inflammatory agents. Through structure\u2212activity relationship studies, a lead compound MD-1 was designed and synthesized, exhibiting significantly improved antiinflammatory activities. Mechanistic studies revealed that MD-1 is a degrader of the p105 subunit of NF-\u03baB. Gene knockdown [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/discovery-of-an-nf-\u03bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2025-07-16T08:50:44+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2025\/07\/20250516-FW.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1280\" \/>\n\t<meta property=\"og:image:height\" content=\"720\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"1 minute\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/#\\\/schema\\\/person\\\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"Discovery of an NF-\u03baB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate\",\"datePublished\":\"2025-07-16T08:50:44+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/\"},\"wordCount\":163,\"publisher\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/#organization\"},\"image\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/wp-content\\\/uploads\\\/sites\\\/33\\\/2025\\\/07\\\/20250516-FW.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/\",\"url\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/discovery-of-an-nf-%ce%bab1-p105-degrader-for-anti-inflammatory-therapy-via-structural-optimization-of-the-coumarin-natural-product-minutuminolate\\\/\",\"name\":\"Discovery of an NF-\u03baB1 p105 Degrader for Anti-Inflammatory Therapy via Structural Optimization of the Coumarin Natural Product Minutuminolate - 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