Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo

Kaoud, Tamer S.; Johnson, William H.; Ebelt, Nancy D.; Piserchio, Andrea; Zamora-Olivares, Diana; Ravenstein, Sabrina X. Van; Pridgen, Jacey R.; Edupuganti, Ramakrishna; Sammons, Rachel M.; Cano, Micael; Warthaka, Mangalika; Harger, Matthew; Tavares, Clint D.J.; Park, Jihyun; Radwan, Mohamed F.; Ren, Pengyu; Anslyn, Eric V.; Tsai, Kenneth Y.; Ghose, Ranajeet; Dalby, Kevin N.

doi:10.1038/s41467-019-12996-8

Cited by 25 publications

(18 citation statements)

References 67 publications

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“…Recent studies have identified a small-molecule inhibitor that covalently binds to a conserved cysteine (C159) in the DRS of ERK2 ( Kaoud et al, 2019 ). This compound selectively blocked the activation of ERK1/2, did not modify other members of the MAP kinase family, and inhibited the proliferation of melanoma cells with BRAF (V600E) mutations that were resistant to BRAF inhibitors ( Kaoud et al, 2019 ). Future studies will be aimed at identifying whether cysteine residues on other proteins may be modified by SF-3-030 to establish their role in cell signaling and growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Martínez

Huang

Samadani

et al. 2020

J Pharmacol Exp Ther

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Constitutively active extracellular signal–regulated kinase (ERK) 1/2 signaling promotes cancer cell proliferation and survival. We previously described a class of compounds containing a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold that targeted ERK2 substrate docking sites and selectively inhibited ERK1/2-dependent functions, including activator protein-1–mediated transcription and growth of cancer cells containing active ERK1/2 due to mutations in Ras G-proteins or BRAF, Proto-oncogene B-RAF (Rapidly Acclerated Fibrosarcoma) kinase. The current study identified chemical features required for biologic activity and global effects on gene and protein levels in A375 melanoma cells containing mutant BRAF (V600E). Saturation transfer difference-NMR and mass spectrometry analyses revealed interactions between a lead compound ( SF-3-030 ) and ERK2, including the formation of a covalent adduct on cysteine 252 that is located near the docking site for ERK/FXF (DEF) motif for substrate recruitment. Cells treated with SF-3-030 showed rapid changes in immediate early gene levels, including DEF motif–containing ERK1/2 substrates in the Fos family. Analysis of transcriptome and proteome changes showed that the SF-3-030 effects overlapped with ATP-competitive or catalytic site inhibitors of MAPK/ERK Kinase 1/2 (MEK1/2) or ERK1/2. Like other ERK1/2 pathway inhibitors, SF-3-030 induced reactive oxygen species (ROS) and genes associated with oxidative stress, including nuclear factor erythroid 2–related factor 2 (NRF2). Whereas the addition of the ROS inhibitor N -acetyl cysteine reversed SF-3-030 –induced ROS and inhibition of A375 cell proliferation, the addition of NRF2 inhibitors has little effect on cell proliferation. These studies provide mechanistic information on a novel chemical scaffold that selectively regulates ERK1/2-targeted transcription factors and inhibits the proliferation of A375 melanoma cells through a ROS-dependent mechanism. SIGNIFICANCE STATEMENT Constitutive activation of the extracellular signal–regulated kinase (ERK1/2) pathway drives the proliferation and survival of many cancer cell types. Given the diversity of cellular functions regulated by ERK1/2, the current studies have examined the mechanism of a novel chemical scaffold that targets ERK2 near a substrate binding site and inhibits select ERK functions. Using transcriptomic and proteomic analyses, we provide a mechanistic basis for how this class of compounds inhibits melanoma cells containing mutated BRAF and active ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Martínez

Huang

Samadani

et al. 2020

J Pharmacol Exp Ther

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“…JNK/AP1 pathway is important in adaptive responses to the MEK inhibitor vemurafenib [164]. JNK inhibition with the small molecule compound BI-78D3 induced apoptosis and inhibited cell growth of BRAF inhibitor-naive and resistant melanoma cells [175]. Melanoma cells treated with the PAK inhibitor PF-3758309 displayed increased activation of JNK, β-catenin, and the mTOR signaling pathway and shRNA-mediated gene silencing JNK and β-catenin further decreased melanoma cell viability [176].…”

Section: Paradoxical Roles Of Jnk In Melanoma Cell Survival Apoptosis and Therapymentioning

confidence: 99%

The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer

Hammouda

Ford

Liu

et al. 2020

Cells

189

114

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The c-Jun N-terminal kinases (JNKs), with its members JNK1, JNK2, and JNK3, is a subfamily of (MAPK) mitogen-activated protein kinases. JNK signaling regulates a wide range of cellular processes, including cell proliferation, differentiation, survival, apoptosis, and inflammation. Dysregulation of JNK pathway is associated with a wide range of immune disorders and cancer. Our objective is to provide a review of JNK proteins and their upstream regulators and downstream effector molecules in common skin disorders, including psoriasis, dermal fibrosis, scleroderma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma.

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“…However, the limitations of these studies were the lack of definitive experimental evidence for the binding interactions between the compounds and ERK2 and the relative low potency of the compounds. Recent studies [ 38 , 39 ] highlighting the design of new type IV inhibitors targeting the DRS on ERK2 will be the topic of discussion in Chap. 10.1007/978-3-030-48283-1_6.…”

Section: Part B: Type IV Kinase Inhibitorsmentioning

confidence: 99%

“…This cysteine is conserved in ERK1/2 but not in p38 or JNK MAP kinases, which is expected to provide some degree of selectivity. More recent studies have identified ERK1/2-targeted compounds that form covalent bonds with a cysteine (C159) located in the D-recruitment site (DRS) outside the ATP-binding site [ 39 ]. The lead compound, BI-78D3, appears to block interactions between ERK2 and its activator MEK1.…”

Section: Part D: Type VI Kinase Inhibitorsmentioning

confidence: 99%

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Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

Martínez

Defnet

Shapiro

2020

Next Generation Kinase Inhibitors

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As described in the previous chapter, most kinase inhibitors that have been developed for use in the clinic act by blocking ATP binding; however, there is growing interest in identifying compounds that target kinase activities and functions without interfering with the conserved features of the ATP-binding site. This chapter will highlight alternative approaches that exploit unique kinase structural features that are being targeted to identify more selective and potent inhibitors. The figure below, adapted from (Sammons et al., Molecular Carcinogenesis 58:1551–1570, 2019), provides a graphical description of the various approaches to manipulate kinase activity. In addition to the type I and II inhibitors, type III kinase inhibitors have been identified to target sites adjacent to the ATP-binding site in the catalytic domain. New information on kinase structure and substrate-binding sites has enabled the identification of type IV kinase inhibitor compounds that target regions outside the catalytic domain. The combination of targeting unique allosteric sites outside the catalytic domain with ATP-targeted compounds has yielded a number of novel bivalent type V kinase inhibitors. Finally, emerging interest in the development of irreversible compounds that form selective covalent interactions with key amino acids involved in kinase functions comprise the class of type VI kinase inhibitors.

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Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo

Cited by 25 publications

References 67 publications

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer

Avoiding or Co-Opting ATP Inhibition: Overview of Type III, IV, V, and VI Kinase Inhibitors

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