Abstract:
:Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1-specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutant RAS Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.
journal_name
Proc Natl Acad Sci U S Aauthors
Vidimar V,Beilhartz GL,Park M,Biancucci M,Kieffer MB,Gius DR,Melnyk RA,Satchell KJFdoi
10.1073/pnas.2000312117subject
Has Abstractpub_date
2020-07-21 00:00:00pages
16938-16948issue
29eissn
0027-8424issn
1091-6490pii
2000312117journal_volume
117pub_type
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