ArticleCommunications biology2021
Engineering subtilisin proteases that specifically degrade active RAS.
Article in Communications biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Engineered subtilisin protease degrades active KRAS in cancer cells leading to differential cell targeting.Research square · 2026Article
- Engineered subtilisin protease degrades active KRAS in cancer cells, leading to differential cell targeting.bioRxiv : the preprint server for biology · 2026Article
- Substrate specificity in a designed RAS-targeting protease is coupled to active site and distal motions.bioRxiv : the preprint server for biology · 2026Article
- Recent advances in targeted degradation in the RAS pathway.Future medicinal chemistry · 2025Review
- Biochemical characterization of immobilized recombinant subtilisin and synthesis and functional characterization of recombinant subtilisin capped silver and zinc oxide nanoparticles.Saudi journal of biological sciences · 2024Article
- Ionizable lipid nanoparticles for RAS protease delivery to inhibit cancer cell proliferation.Journal of controlled release : official journal of the Controlled Release Society · 2024Article
- Intracellular Protein Delivery: Approaches, Challenges, and Clinical Applications.BME frontiers · 2024Review
- RAS degraders: The new frontier for RAS-driven cancers.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Review
- Design and characterization of a protein fold switching network.Nature communications · 2023Article
- Proteolytic pan-RAS Cleavage Leads to Tumor Regression in Patient-derived Pancreatic Cancer Xenografts.Molecular cancer therapeutics · 2022Article
- Intrinsically disordered proteins: Ensembles at the limits of Anfinsen's dogma.Biophysics reviews · 2022Review
- RAS specific protease induces irreversible growth arrest via p27 in several KRAS mutant colorectal cancer cell lines.Scientific reports · 2021Article
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 3 countries.
Funding
Abstract
We describe the design, kinetic properties, and structures of engineered subtilisin proteases that degrade the active form of RAS by cleaving a conserved sequence in switch 2. RAS is a signaling protein that, when mutated, drives a third of human cancers. To generate high specificity for the RAS target sequence, the active site was modified to be dependent on a cofactor (imidazole or nitrite) and protease sub-sites were engineered to create a linkage between substrate and cofactor binding. Selective proteolysis of active RAS arises from a 2-step process wherein sub-site interactions promote productive binding of the cofactor, enabling cleavage. Proteases engineered in this way specifically cleave active RAS in vitro, deplete the level of RAS in a bacterial reporter system, and also degrade RAS in human cell culture. Although these proteases target active RAS, the underlying design principles are fundamental and will be adaptable to many target proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.