Development of a RIPK1 degrader to enhance antitumor immunity
Abstract The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocke...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55006-2 |
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| _version_ | 1846112453119705088 |
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| author | Xin Yu Dong Lu Xiaoli Qi Rishi Ram Paudel Hanfeng Lin Bryan L. Holloman Feng Jin Longyong Xu Lang Ding Weiyi Peng Meng C. Wang Xi Chen Jin Wang |
| author_facet | Xin Yu Dong Lu Xiaoli Qi Rishi Ram Paudel Hanfeng Lin Bryan L. Holloman Feng Jin Longyong Xu Lang Ding Weiyi Peng Meng C. Wang Xi Chen Jin Wang |
| author_sort | Xin Yu |
| collection | DOAJ |
| description | Abstract The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy. |
| format | Article |
| id | doaj-art-f591d40495ea436785c1c2830080331d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f591d40495ea436785c1c2830080331d2024-12-22T12:35:57ZengNature PortfolioNature Communications2041-17232024-12-0115111410.1038/s41467-024-55006-2Development of a RIPK1 degrader to enhance antitumor immunityXin Yu0Dong Lu1Xiaoli Qi2Rishi Ram Paudel3Hanfeng Lin4Bryan L. Holloman5Feng Jin6Longyong Xu7Lang Ding8Weiyi Peng9Meng C. Wang10Xi Chen11Jin Wang12The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineDepartment of Molecular and Cellular Biology, Baylor College of MedicineHoward Hughes Medical Institute, Janelia Research CampusDepartment of Biology and Biochemistry, University of HoustonHoward Hughes Medical Institute, Janelia Research CampusDepartment of Molecular and Cellular Biology, Baylor College of MedicineThe Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of MedicineAbstract The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.https://doi.org/10.1038/s41467-024-55006-2 |
| spellingShingle | Xin Yu Dong Lu Xiaoli Qi Rishi Ram Paudel Hanfeng Lin Bryan L. Holloman Feng Jin Longyong Xu Lang Ding Weiyi Peng Meng C. Wang Xi Chen Jin Wang Development of a RIPK1 degrader to enhance antitumor immunity Nature Communications |
| title | Development of a RIPK1 degrader to enhance antitumor immunity |
| title_full | Development of a RIPK1 degrader to enhance antitumor immunity |
| title_fullStr | Development of a RIPK1 degrader to enhance antitumor immunity |
| title_full_unstemmed | Development of a RIPK1 degrader to enhance antitumor immunity |
| title_short | Development of a RIPK1 degrader to enhance antitumor immunity |
| title_sort | development of a ripk1 degrader to enhance antitumor immunity |
| url | https://doi.org/10.1038/s41467-024-55006-2 |
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