A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens.

Autor: Mattson NM; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Chan AKN; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.; Division of Epigenetic and Transcriptional Engineering, Beckman Research Institute, City of Hope, Duarte, CA, USA., Miyashita K; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Mukhaleva E; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA., Chang WH; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Yang L; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.; Division of Epigenetic and Transcriptional Engineering, Beckman Research Institute, City of Hope, Duarte, CA, USA., Ma N; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA., Wang Y; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA., Pokharel SP; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.; Division of Epigenetic and Transcriptional Engineering, Beckman Research Institute, City of Hope, Duarte, CA, USA., Li M; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Liu Q; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Xu X; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Chen R; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Singh P; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Zhang L; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Elsayed Z; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Chen B; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Keen D; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Pirrotte P; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA., Rosen ST; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Chen J; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA.; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., LaBarge MA; City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA, USA., Shively JE; City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Department of Immunology and Theranostics, Beckman Research Institute, City of Hope, Duarte, CA, USA., Vaidehi N; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Rockne RC; Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA.; City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Feng M; City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA., Chen CW; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA, USA. cweichen@coh.org.; Division of Epigenetic and Transcriptional Engineering, Beckman Research Institute, City of Hope, Duarte, CA, USA. cweichen@coh.org.; City of Hope Comprehensive Cancer Center, Duarte, CA, USA. cweichen@coh.org.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Mar; Vol. 31 (3), pp. 465-475. Date of Electronic Publication: 2024 Feb 05.
DOI: 10.1038/s41594-024-01211-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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