Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives
Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2419925 |
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| author | Yong-Sung Choi Yoon-Jung Kim Yeram Jeon Jong Soon Kang Juhee Lee Eunmi Hong Young-Hoon Park Wantae Kim Boksik Cha Raok Jeon |
| author_facet | Yong-Sung Choi Yoon-Jung Kim Yeram Jeon Jong Soon Kang Juhee Lee Eunmi Hong Young-Hoon Park Wantae Kim Boksik Cha Raok Jeon |
| author_sort | Yong-Sung Choi |
| collection | DOAJ |
| description | Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma. |
| format | Article |
| id | doaj-art-d1b6d6a6c1ae4cfc87ac106339eee178 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-d1b6d6a6c1ae4cfc87ac106339eee1782025-08-20T02:35:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2419925Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivativesYong-Sung Choi0Yoon-Jung Kim1Yeram Jeon2Jong Soon Kang3Juhee Lee4Eunmi Hong5Young-Hoon Park6Wantae Kim7Boksik Cha8Raok Jeon9College of Pharmacy, Sookmyung Women’s University, Seoul, KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul, KoreaDepartment of Biochemistry, Chungnam National University, Daejeon, KoreaLaboratory Animal Resource and Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, KoreaDaegu-Gyeongbuk Medical Innovation Foundation, Daegu, KoreaDaegu-Gyeongbuk Medical Innovation Foundation, Daegu, KoreaDaegu-Gyeongbuk Medical Innovation Foundation, Daegu, KoreaDepartment of Biochemistry, Chungnam National University, Daejeon, KoreaDaegu-Gyeongbuk Medical Innovation Foundation, Daegu, KoreaCollege of Pharmacy, Sookmyung Women’s University, Seoul, KoreaTranscriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.https://www.tandfonline.com/doi/10.1080/14756366.2024.2419925Hippo pathwayTEAD inhibitorpalmitate pocketrational designmesothelioma |
| spellingShingle | Yong-Sung Choi Yoon-Jung Kim Yeram Jeon Jong Soon Kang Juhee Lee Eunmi Hong Young-Hoon Park Wantae Kim Boksik Cha Raok Jeon Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives Journal of Enzyme Inhibition and Medicinal Chemistry Hippo pathway TEAD inhibitor palmitate pocket rational design mesothelioma |
| title | Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives |
| title_full | Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives |
| title_fullStr | Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives |
| title_full_unstemmed | Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives |
| title_short | Exploring structural and biological insights of TEAD through rational design and synthesis of niflumic acid derivatives |
| title_sort | exploring structural and biological insights of tead through rational design and synthesis of niflumic acid derivatives |
| topic | Hippo pathway TEAD inhibitor palmitate pocket rational design mesothelioma |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2419925 |
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