Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange.
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ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2017-07-14
Date Accepted
2017-05-30
Abstract
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.
Citation
Nature communications, 2017, 8 pp. 16111 - ?
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Chromosomal Translocations and Intracellular Antibody Therapeutics