4QYY

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase State

Summary for 4QYY

• Entry DOI: 10.2210/pdb4qyy/pdb
• Descriptor: Mitogen-activated protein kinase 1, (3R)-1-{2-[4-(4-acetylphenyl)piperazin-1-yl]-2-oxoethyl}-N-(3-chloro-4-hydroxyphenyl)pyrrolidine-3-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, map kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P63086
• Total number of polymer chains: 1
• Total formula weight: 43003.67

Authors

Deng, Y.,Shipps, G.W.,Cooper, A.,English, J.M.,Annis, D.A.,Carr, D.,Nan, Y.,Wang, T.,Zhu, Y.H.,Chuang, C.,Dayananth, P.,Hruza, A.W.,Xiao, L.,Jin, W.,Kirschmeier, P.,Windsor, W.T.,Samatar, A.A. (deposition date: 2014-07-26, release date: 2014-11-12, Last modification date: 2023-09-20)

Primary citation

Deng, Y.,Shipps, G.W.,Cooper, A.,English, J.M.,Annis, D.A.,Carr, D.,Nan, Y.,Wang, T.,Zhu, H.Y.,Chuang, C.C.,Dayananth, P.,Hruza, A.W.,Xiao, L.,Jin, W.,Kirschmeier, P.,Windsor, W.T.,Samatar, A.A.
Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase.
J.Med.Chem., 57:8817-8826, 2014

PubMed Abstract: An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue 1 that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound 4 as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound 4 to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which 4 can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity.

PubMed: 25313996
DOI: 10.1021/jm500847m

Experimental method

X-RAY DIFFRACTION (1.65 Å)