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Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.
- Source :
-
Nature [Nature] 2016 Sep 01; Vol. 537 (7618), pp. 112-116. Date of Electronic Publication: 2016 Aug 24. - Publication Year :
- 2016
-
Abstract
- Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.
- Subjects :
- Alleles
Allosteric Regulation drug effects
Cell Line
Enzyme Stability drug effects
Humans
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases chemistry
Mitogen-Activated Protein Kinase Kinases metabolism
Models, Molecular
Mutation
Neoplasms drug therapy
Neoplasms enzymology
Neoplasms genetics
Neoplasms metabolism
Oncogenes genetics
Phosphorylation drug effects
Protein Binding
Protein Conformation drug effects
Protein Multimerization drug effects
Protein Serine-Threonine Kinases genetics
Pyridones pharmacology
Pyrimidinones pharmacology
raf Kinases chemistry
raf Kinases metabolism
ras Proteins genetics
ras Proteins metabolism
MAP Kinase Signaling System drug effects
Oncogenes drug effects
Protein Serine-Threonine Kinases chemistry
Protein Serine-Threonine Kinases metabolism
Quinazolines pharmacology
ras Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 537
- Issue :
- 7618
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 27556948
- Full Text :
- https://doi.org/10.1038/nature19327