RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site

Katarzyna Z. Haza, Heather L. Martin, Ajinkya Rao, Amy L. Turner, Sophie E. Saunders, Britta Petersen, Christian Tiede, Kevin Tipping, Anna A. Tang, Modupe Ajayi, Thomas Taylor, Maia Harvey, Keri M. Fishwick, Thomas L. Adams, Thembaninkosi G. Gaule, Chi H. Trinh, Matthew Johnson, Alexander L. Breeze, Thomas A. Edwards, Michael J. McPherson and Darren C. Tomlinson ()
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Katarzyna Z. Haza: University of Leeds
Heather L. Martin: University of Leeds
Ajinkya Rao: University of Leeds
Amy L. Turner: University of Leeds
Sophie E. Saunders: University of Leeds
Britta Petersen: University of Leeds
Christian Tiede: University of Leeds
Kevin Tipping: University of Leeds
Anna A. Tang: University of Leeds
Modupe Ajayi: University of Leeds
Thomas Taylor: University of Leeds
Maia Harvey: University of Leeds
Keri M. Fishwick: University of Leeds
Thomas L. Adams: University of Leeds
Thembaninkosi G. Gaule: University of Leeds
Chi H. Trinh: University of Leeds
Matthew Johnson: Avacta Life Sciences
Alexander L. Breeze: University of Leeds
Thomas A. Edwards: University of Leeds
Michael J. McPherson: University of Leeds
Darren C. Tomlinson: University of Leeds

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24316-0

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DOI: 10.1038/s41467-021-24316-0

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