5KKR

KSR2:MEK1 Complex Bound to the Small Molecule APS-2-79

Summary for 5KKR

• Entry DOI: 10.2210/pdb5kkr/pdb
• Descriptor: Kinase suppressor of Ras 2, Dual specificity mitogen-activated protein kinase kinase 1, 6,7-dimethoxy-~{N}-(2-methyl-4-phenoxy-phenyl)quinazolin-4-amine (3 entities in total)
• Functional Keywords: kinase suppressor of ras small molecule complex, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 80798.08

Authors

Dhawan, N.S.,Scopton, A.P.,Dar, A.C. (deposition date: 2016-06-22, release date: 2016-08-31, Last modification date: 2023-09-27)

Primary citation

Dhawan, N.S.,Scopton, A.P.,Dar, A.C.
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.
Nature, 537:112-116, 2016

PubMed 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.

PubMed: 27556948
DOI: 10.1038/nature19327

Experimental method

X-RAY DIFFRACTION (3.509 Å)