Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange.
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Date
2017-07-14ICR Author
Author
Guillard, S
Kolasinska-Zwierz, P
Debreczeni, J
Breed, J
Zhang, J
Bery, N
Marwood, R
Tart, J
Overman, R
Stocki, P
Mistry, B
Phillips, C
Rabbitts, T
Jackson, R
Minter, R
Type
Journal Article
Metadata
Show full item recordAbstract
Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a Kd of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.
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Subject
HCT116 Cells
Humans
ras Proteins
Antibodies
Cell Proliferation
Molecular Structure
Ankyrin Repeat
Drug Design
HEK293 Cells
Molecular Targeted Therapy
Research team
Chromosomal Translocations and Intracellular Antibody Therapeutics
Language
eng
Date accepted
2017-05-30
License start date
2017-07-14
Citation
Nature communications, 2017, 8 pp. 16111 - ?
Publisher
NATURE PUBLISHING GROUP