Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling
A class of small molecules that stabilize a previously unrecognized inactive state of KSR is reported; the agonists synergize with MEK inhibitors to prevent growth of Ras mutant cell lines. Novel KSR antagonists KSR (kinase suppressor of Ras) is a scaffold protein and pseudokinase for the RAS-activa...
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| Published in | Nature (London) Vol. 537; no. 7618; pp. 112 - 116 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
London
Nature Publishing Group UK
01.09.2016
Nature Publishing Group |
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| Online Access | Get full text |
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| Abstract | A class of small molecules that stabilize a previously unrecognized inactive state of KSR is reported; the agonists synergize with MEK inhibitors to prevent growth of Ras mutant cell lines.
Novel KSR antagonists
KSR (kinase suppressor of Ras) is a scaffold protein and pseudokinase for the RAS-activated MAP kinase pathway that is allosterically regulated through dimerization with the RAF kinase. Here Arvin Dar and colleagues use a structure-based approach to develop a class of small molecules that stabilize a previously unrecognized inactive state of KSR. These KSR antagonists can synergize with MEK inhibitors to inhibit growth of RAS mutant cell lines, and offer a potential therapeutic approach for targeting oncogenic RAS signalling in cancer.
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
1
. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes
2
. Kinase suppressor of Ras (KSR) is a MAPK scaffold
3
,
4
,
5
that is subject to allosteric regulation through dimerization with RAF
6
,
7
. 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. |
|---|---|
| AbstractList | 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. In conclusion, 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. 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 (mitogenactivated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Rasmutant 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. 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 1 . Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes 2 . Kinase suppressor of Ras (KSR) is a MAPK scaffold 3 – 5 that is subject to allosteric regulation through dimerization with RAF 6 , 7 . 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. 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. A class of small molecules that stabilize a previously unrecognized inactive state of KSR is reported; the agonists synergize with MEK inhibitors to prevent growth of Ras mutant cell lines. Novel KSR antagonists KSR (kinase suppressor of Ras) is a scaffold protein and pseudokinase for the RAS-activated MAP kinase pathway that is allosterically regulated through dimerization with the RAF kinase. Here Arvin Dar and colleagues use a structure-based approach to develop a class of small molecules that stabilize a previously unrecognized inactive state of KSR. These KSR antagonists can synergize with MEK inhibitors to inhibit growth of RAS mutant cell lines, and offer a potential therapeutic approach for targeting oncogenic RAS signalling in cancer. 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 1 . Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes 2 . Kinase suppressor of Ras (KSR) is a MAPK scaffold 3 , 4 , 5 that is subject to allosteric regulation through dimerization with RAF 6 , 7 . 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. 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.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. |
| Audience | Academic |
| Author | Dar, Arvin C. Dhawan, Neil S. Scopton, Alex P. |
| AuthorAffiliation | 2 Department of Structural and Chemical Biology, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA 1 Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA |
| AuthorAffiliation_xml | – name: 2 Department of Structural and Chemical Biology, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA – name: 1 Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA |
| Author_xml | – sequence: 1 givenname: Neil S. surname: Dhawan fullname: Dhawan, Neil S. organization: Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, Department of Structural and Chemical Biology, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai – sequence: 2 givenname: Alex P. surname: Scopton fullname: Scopton, Alex P. organization: Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, Department of Structural and Chemical Biology, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai – sequence: 3 givenname: Arvin C. surname: Dar fullname: Dar, Arvin C. email: arvin.dar@mssm.edu organization: Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, Department of Structural and Chemical Biology, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27556948$$D View this record in MEDLINE/PubMed https://www.osti.gov/servlets/purl/1368230$$D View this record in Osti.gov |
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| CODEN | NATUAS |
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| ContentType | Journal Article |
| Copyright | Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 2016 COPYRIGHT 2016 Nature Publishing Group Copyright Nature Publishing Group Sep 1, 2016 |
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| DOI | 10.1038/nature19327 |
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| Snippet | A class of small molecules that stabilize a previously unrecognized inactive state of KSR is reported; the agonists synergize with MEK inhibitors to prevent... 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... 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... |
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| SubjectTerms | 13 631/45/275 631/67/1059/602 631/80/86/2368 631/92 82 82/83 96 96/98 Alleles Allosteric Regulation - drug effects BASIC BIOLOGICAL SCIENCES Cancer Cancer treatment Care and treatment Cell Line Chemical biology Crystal structure Deregulation Enzyme Stability - drug effects Genes Growth factor signalling Humanities and Social Sciences Humans Kinases letter Ligands MAP Kinase Signaling System - drug effects Methods Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinase Kinases - chemistry Mitogen-Activated Protein Kinase Kinases - metabolism Models, Molecular multidisciplinary Mutation Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - genetics Neoplasms - metabolism Oncogenes - drug effects Oncogenes - genetics Phosphorylation Phosphorylation - drug effects Phosphotransferases Physiological aspects Protein Binding Protein Conformation - drug effects Protein Multimerization - drug effects Protein-Serine-Threonine Kinases - chemistry Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Pyridones - pharmacology Pyrimidinones - pharmacology Quinazolines - pharmacology raf Kinases - chemistry raf Kinases - metabolism Ras genes ras Proteins - antagonists & inhibitors ras Proteins - genetics ras Proteins - metabolism Science Signal transduction Targeted therapies |
| Title | Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling |
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