Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange

被引：67

作者：

Guillard, Sandrine ^{[1
]}

Kolasinska-Zwierz, Paulina ^{[1
]}

Debreczeni, Judit ^{[2
]}

Breed, Jason ^{[2
]}

Zhang, Jing ^{[3
]}

Bery, Nicolas ^{[3
]}

Marwood, Rose ^{[1
]}

Tart, Jon ^{[2
]}

Overman, Ross ^{[2
]}

Stocki, Pawel ^{[1
]}

Mistry, Bina ^{[1
]}

Phillips, Christopher ^{[2
]}

Rabbitts, Terence ^{[3
]}

Jackson, Ronald ^{[1
]}

Minter, Ralph ^{[1
]}

机构：

[1] MedImmune, Antibody Discovery & Prot Engn, Milstein Bldg,Granta Pk, Cambridge CB21 6GH, England

[2] AstraZeneca, Discovery Sci Innovat Med & Early Dev, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, England

[3] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

BLADDER-CARCINOMA ONCOGENE; SIGNAL-TRANSDUCTION; PROTEINS; ACTIVATION; KRAS; COMPLEX; CANCER; SOS; MUTATIONS; HOMOLOG;

D O I：

10.1038/ncomms16111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 43 条

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