KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe

被引：66

作者：

Bery, Nicolas ^{[1
]}

Legg, Sandrine ^{[2
]}

Debreczeni, Judit ^{[3
]}

Breed, Jason ^{[3
]}

Embrey, Kevin ^{[3
]}

Stubbs, Christopher ^{[3
]}

Kolasinska-Zwierz, Paulina ^{[2
]}

Barrett, Nathalie ^{[2
]}

Marwood, Rose ^{[2
]}

Watson, Jo ^{[2
]}

Tart, Jon ^{[3
]}

Overman, Ross ^{[3
]}

Miller, Ami ^{[1
]}

Phillips, Christopher ^{[3
]}

MinterH, Ralph ^{[2
]}

Rabbitts, Terence H. ^{[1
]}

机构：

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

[2] R&D BioPharmaceut, Antibody Discovery & Prot Engn, Milstein Bldg Granta Pk, Cambridge, England

[3] AstraZeneca, Discovery Sci, R&D BioPharmaceut, Darwin Bldg,Cambridge Sci Pk,Milton Rd, Cambridge CB4 OWG, England

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

英国惠康基金;

关键词：

K-RAS; MUTANT; MUTATIONS; PROTEINS; CANCER; DIMERS;

D O I：

10.1038/s41467-019-10419-2

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：

Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix alpha 3/loop 7/helix alpha 4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the alpha 3/loop 7/alpha 4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.

引用

页数：11

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