A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation

Rachel M. Sammons, Nicole A. Perry, Yangmei Li, Eun Jeong Cho, Andrea Piserchio, Diana P. Zamora-Olivares, Ranajeet Ghose, Tamer S. Kaoud, Ginamarie Debevec, Chandra Bartholomeusz, Vsevolod V. Gurevich, Tina M. Iverson, Marc Giulianotti, Richard A. Houghten, Kevin Dalby

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Extracellular signal-regulated kinases (ERK1/2) are mitogen-activated protein kinases (MAPKs) that play a pro-tumorigenic role in numerous cancers. ERK1/2 possess two protein-docking sites that are distinct from the active site: the D-recruitment site (DRS) and the F-recruitment site. These docking sites facilitate substrate recognition, intracellular localization, signaling specificity, and protein complex assembly. Targeting these sites on ERK in a therapeutic context may overcome many problems associated with traditional ATP-competitive inhibitors. Here, we identified a new class of inhibitors that target the ERK DRS by screening a synthetic combinatorial library of more than 30 million compounds. The screen detects the competitive displacement of a fluorescent peptide from the DRS of ERK2. The top molecular scaffold from the screen was optimized for structure-activity relationship by positional scanning of different functional groups. This resulted in 10 compounds with similar binding affinities and a shared core structure consisting of a tertiary amine hub with three functionalized cyclic guanidino branches. Compound 2507-1 inhibited ERK2 from phosphorylating a DRS-targeting substrate and prevented the phosphorylation of ERK2 by a constitutively active MEK1 (MAPK/ERK kinase 1) mutant. Interaction between an analogue, 2507-8, and the ERK2 DRS was confirmed by nuclear magnetic resonance and X-ray crystallography. 2507-8 forms critical interactions at the common docking domain residue Asp319 via an arginine-like moiety that is shared by all 10 hits, suggesting a common binding mode. The structural and biochemical insights reported here provide the basis for developing new ERK inhibitors that are not ATP-competitive but instead function by disrupting critical protein-protein interactions.

Original languageEnglish (US)
Pages (from-to)1183-1194
Number of pages12
JournalACS chemical biology
Volume14
Issue number6
DOIs
StatePublished - Jun 21 2019

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Phosphorylation
Chemical activation
Substrates
Proteins
Adenosine Triphosphate
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase 1
X ray crystallography
X Ray Crystallography
Extracellular Signal-Regulated MAP Kinases
Structure-Activity Relationship
Mitogen-Activated Protein Kinases
Scaffolds
Functional groups
Amines
Arginine
Catalytic Domain
Screening
Phosphotransferases
Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation. / Sammons, Rachel M.; Perry, Nicole A.; Li, Yangmei; Cho, Eun Jeong; Piserchio, Andrea; Zamora-Olivares, Diana P.; Ghose, Ranajeet; Kaoud, Tamer S.; Debevec, Ginamarie; Bartholomeusz, Chandra; Gurevich, Vsevolod V.; Iverson, Tina M.; Giulianotti, Marc; Houghten, Richard A.; Dalby, Kevin.

In: ACS chemical biology, Vol. 14, No. 6, 21.06.2019, p. 1183-1194.

Research output: Contribution to journalArticle

Sammons, RM, Perry, NA, Li, Y, Cho, EJ, Piserchio, A, Zamora-Olivares, DP, Ghose, R, Kaoud, TS, Debevec, G, Bartholomeusz, C, Gurevich, VV, Iverson, TM, Giulianotti, M, Houghten, RA & Dalby, K 2019, 'A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation', ACS chemical biology, vol. 14, no. 6, pp. 1183-1194. https://doi.org/10.1021/acschembio.9b00093
Sammons, Rachel M. ; Perry, Nicole A. ; Li, Yangmei ; Cho, Eun Jeong ; Piserchio, Andrea ; Zamora-Olivares, Diana P. ; Ghose, Ranajeet ; Kaoud, Tamer S. ; Debevec, Ginamarie ; Bartholomeusz, Chandra ; Gurevich, Vsevolod V. ; Iverson, Tina M. ; Giulianotti, Marc ; Houghten, Richard A. ; Dalby, Kevin. / A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation. In: ACS chemical biology. 2019 ; Vol. 14, No. 6. pp. 1183-1194.
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abstract = "Extracellular signal-regulated kinases (ERK1/2) are mitogen-activated protein kinases (MAPKs) that play a pro-tumorigenic role in numerous cancers. ERK1/2 possess two protein-docking sites that are distinct from the active site: the D-recruitment site (DRS) and the F-recruitment site. These docking sites facilitate substrate recognition, intracellular localization, signaling specificity, and protein complex assembly. Targeting these sites on ERK in a therapeutic context may overcome many problems associated with traditional ATP-competitive inhibitors. Here, we identified a new class of inhibitors that target the ERK DRS by screening a synthetic combinatorial library of more than 30 million compounds. The screen detects the competitive displacement of a fluorescent peptide from the DRS of ERK2. The top molecular scaffold from the screen was optimized for structure-activity relationship by positional scanning of different functional groups. This resulted in 10 compounds with similar binding affinities and a shared core structure consisting of a tertiary amine hub with three functionalized cyclic guanidino branches. Compound 2507-1 inhibited ERK2 from phosphorylating a DRS-targeting substrate and prevented the phosphorylation of ERK2 by a constitutively active MEK1 (MAPK/ERK kinase 1) mutant. Interaction between an analogue, 2507-8, and the ERK2 DRS was confirmed by nuclear magnetic resonance and X-ray crystallography. 2507-8 forms critical interactions at the common docking domain residue Asp319 via an arginine-like moiety that is shared by all 10 hits, suggesting a common binding mode. The structural and biochemical insights reported here provide the basis for developing new ERK inhibitors that are not ATP-competitive but instead function by disrupting critical protein-protein interactions.",
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AU - Perry, Nicole A.

AU - Li, Yangmei

AU - Cho, Eun Jeong

AU - Piserchio, Andrea

AU - Zamora-Olivares, Diana P.

AU - Ghose, Ranajeet

AU - Kaoud, Tamer S.

AU - Debevec, Ginamarie

AU - Bartholomeusz, Chandra

AU - Gurevich, Vsevolod V.

AU - Iverson, Tina M.

AU - Giulianotti, Marc

AU - Houghten, Richard A.

AU - Dalby, Kevin

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