dc.contributor.author | Cruz-Migoni, A | |
dc.contributor.author | Canning, P | |
dc.contributor.author | Quevedo, CE | |
dc.contributor.author | Bataille, CJR | |
dc.contributor.author | Bery, N | |
dc.contributor.author | Miller, A | |
dc.contributor.author | Russell, AJ | |
dc.contributor.author | Phillips, SEV | |
dc.contributor.author | Carr, SB | |
dc.contributor.author | Rabbitts, TH | |
dc.date.accessioned | 2020-12-21T11:21:20Z | |
dc.date.issued | 2019-02-12 | |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (7), pp. 2545 - 2550 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4258 | |
dc.identifier.eissn | 1091-6490 | |
dc.identifier.doi | 10.1073/pnas.1811360116 | |
dc.description.abstract | The RAS gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein-protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules. | |
dc.format | Print-Electronic | |
dc.format.extent | 2545 - 2550 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATL ACAD SCIENCES | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Oncogene Protein p21(ras) | |
dc.subject | Antineoplastic Agents | |
dc.subject | Crystallography, X-Ray | |
dc.subject | Surface Plasmon Resonance | |
dc.subject | Molecular Structure | |
dc.subject | Protein Binding | |
dc.subject | Drug Development | |
dc.title | Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1073/pnas.1811360116 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-02 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Proceedings of the National Academy of Sciences of the United States of America | |
pubs.issue | 7 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Chromosomal Translocations and Intracellular Antibody Therapeutics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Chromosomal Translocations and Intracellular Antibody Therapeutics | |
pubs.publication-status | Published | |
pubs.volume | 116 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Chromosomal Translocations and Intracellular Antibody Therapeutics | |
dc.contributor.icrauthor | Rabbitts, Terence | |