1. RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site.
- Author
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Haza KZ, Martin HL, Rao A, Turner AL, Saunders SE, Petersen B, Tiede C, Tipping K, Tang AA, Ajayi M, Taylor T, Harvey M, Fishwick KM, Adams TL, Gaule TG, Trinh CH, Johnson M, Breeze AL, Edwards TA, McPherson MJ, and Tomlinson DC
- Subjects
- Allosteric Site, Biological Products chemistry, Humans, Neoplasms chemistry, Neoplasms enzymology, Signal Transduction, ras Proteins metabolism, Biological Products pharmacology, Cell Surface Display Techniques methods, Drug Discovery methods, Neoplasms drug therapy, ras Proteins antagonists & inhibitors
- Abstract
RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.
- Published
- 2021
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