A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens
The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results...
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| Veröffentlicht in: | Nature structural & molecular biology 2024-03, Vol.31 (3), p.465-475 |
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| creator | Mattson, Nicole M. Chan, Anthony K. N. Miyashita, Kazuya Mukhaleva, Elizaveta Chang, Wen-Han Yang, Lu Ma, Ning Wang, Yingyu Pokharel, Sheela Pangeni Li, Mingli Liu, Qiao Xu, Xiaobao Chen, Renee Singh, Priyanka Zhang, Leisi Elsayed, Zeinab Chen, Bryan Keen, Denise Pirrotte, Patrick Rosen, Steven. T. Chen, Jianjun LaBarge, Mark A. Shively, John E. Vaidehi, Nagarajan Rockne, Russell C. Feng, Mingye Chen, Chun-Wei |
| description | The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.
Here the authors reveal the role of integrin αV and its β-propeller domain in cancer maintenance and identify a novel class of inhibitors that disrupt integrin heterodimer stability via a CRISPR-tiling-instructed computer-aided (CRISPR-TICA) pipeline. |
| doi_str_mv | 10.1038/s41594-024-01211-y |
| format | Article |
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Here the authors reveal the role of integrin αV and its β-propeller domain in cancer maintenance and identify a novel class of inhibitors that disrupt integrin heterodimer stability via a CRISPR-tiling-instructed computer-aided (CRISPR-TICA) pipeline.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-024-01211-y</identifier><identifier>PMID: 38316881</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/154 ; 631/1647/2163 ; 692/699/67 ; Accessibility ; Apoptosis ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Cancer ; Cell Membrane ; Cell surface ; Clustered Regularly Interspaced Short Palindromic Repeats - genetics ; Compounds ; CRISPR ; Dimerization ; Drug discovery ; Genetic screening ; Humans ; Life Sciences ; Membrane Biology ; Protein Structure ; Proteomes ; Stability ; Tiling</subject><ispartof>Nature structural & molecular biology, 2024-03, Vol.31 (3), p.465-475</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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N.</creatorcontrib><creatorcontrib>Miyashita, Kazuya</creatorcontrib><creatorcontrib>Mukhaleva, Elizaveta</creatorcontrib><creatorcontrib>Chang, Wen-Han</creatorcontrib><creatorcontrib>Yang, Lu</creatorcontrib><creatorcontrib>Ma, Ning</creatorcontrib><creatorcontrib>Wang, Yingyu</creatorcontrib><creatorcontrib>Pokharel, Sheela Pangeni</creatorcontrib><creatorcontrib>Li, Mingli</creatorcontrib><creatorcontrib>Liu, Qiao</creatorcontrib><creatorcontrib>Xu, Xiaobao</creatorcontrib><creatorcontrib>Chen, Renee</creatorcontrib><creatorcontrib>Singh, Priyanka</creatorcontrib><creatorcontrib>Zhang, Leisi</creatorcontrib><creatorcontrib>Elsayed, Zeinab</creatorcontrib><creatorcontrib>Chen, Bryan</creatorcontrib><creatorcontrib>Keen, Denise</creatorcontrib><creatorcontrib>Pirrotte, Patrick</creatorcontrib><creatorcontrib>Rosen, Steven. 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Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.
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Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin β5) as the essential integrin α/β pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the β-propeller domain of ITGAV for integrin αVβ5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the β-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVβ5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.
Here the authors reveal the role of integrin αV and its β-propeller domain in cancer maintenance and identify a novel class of inhibitors that disrupt integrin heterodimer stability via a CRISPR-tiling-instructed computer-aided (CRISPR-TICA) pipeline.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38316881</pmid><doi>10.1038/s41594-024-01211-y</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8100-8132</orcidid><orcidid>https://orcid.org/0000-0002-7091-1294</orcidid><orcidid>https://orcid.org/0000-0002-1557-159X</orcidid><orcidid>https://orcid.org/0000-0002-8737-6830</orcidid><orcidid>https://orcid.org/0000-0001-5881-3387</orcidid><orcidid>https://orcid.org/0000-0003-4653-7797</orcidid><orcidid>https://orcid.org/0000-0003-3749-2902</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/154 631/1647/2163 692/699/67 Accessibility Apoptosis Biochemistry Biological Microscopy Biomedical and Life Sciences Cancer Cell Membrane Cell surface Clustered Regularly Interspaced Short Palindromic Repeats - genetics Compounds CRISPR Dimerization Drug discovery Genetic screening Humans Life Sciences Membrane Biology Protein Structure Proteomes Stability Tiling |
| title | A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens |
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