Abstract:Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographi… Show more
“…It is well known that kinases may adopt multiple conformations depending on the ligand structures. ERK enzymes are not an exception since, for instance, it has been reported that the isoform ERK-2 may adopt multiple conformations depending on the nature of the ligands [65]. In both 4QTA and 4QTB, Tyr27/Tyr30 are present as ‘in’ conformations.…”
Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer. The ERK-1/2 inhibitors are thus considered as potential agents for cancer therapy. Multitarget quantitative structure–activity relationship (mt-QSAR) models based on the Box–Jenkins approach were developed with a dataset containing 6400 ERK inhibitors assayed under different experimental conditions. The first mt-QSAR linear model was built with linear discriminant analysis (LDA) and provided information regarding the structural requirements for better activity. This linear model was also utilised for a fragment analysis to estimate the contributions of ring fragments towards ERK inhibition. Then, the random forest (RF) technique was employed to produce highly predictive non-linear mt-QSAR models, which were used for screening the Asinex kinase library and identify the most potential virtual hits. The fragment analysis results justified the selection of the hits retrieved through such virtual screening. The latter were subsequently subjected to molecular docking and molecular dynamics simulations to understand their possible interactions with ERK enzymes. The present work, which utilises in-silico techniques such as multitarget chemometric modelling, fragment analysis, virtual screening, molecular docking and dynamics, may provide important guidelines to facilitate the discovery of novel ERK inhibitors.
“…It is well known that kinases may adopt multiple conformations depending on the ligand structures. ERK enzymes are not an exception since, for instance, it has been reported that the isoform ERK-2 may adopt multiple conformations depending on the nature of the ligands [65]. In both 4QTA and 4QTB, Tyr27/Tyr30 are present as ‘in’ conformations.…”
Two isoforms of extracellular regulated kinase (ERK), namely ERK-1 and ERK-2, are associated with several cellular processes, the aberration of which leads to cancer. The ERK-1/2 inhibitors are thus considered as potential agents for cancer therapy. Multitarget quantitative structure–activity relationship (mt-QSAR) models based on the Box–Jenkins approach were developed with a dataset containing 6400 ERK inhibitors assayed under different experimental conditions. The first mt-QSAR linear model was built with linear discriminant analysis (LDA) and provided information regarding the structural requirements for better activity. This linear model was also utilised for a fragment analysis to estimate the contributions of ring fragments towards ERK inhibition. Then, the random forest (RF) technique was employed to produce highly predictive non-linear mt-QSAR models, which were used for screening the Asinex kinase library and identify the most potential virtual hits. The fragment analysis results justified the selection of the hits retrieved through such virtual screening. The latter were subsequently subjected to molecular docking and molecular dynamics simulations to understand their possible interactions with ERK enzymes. The present work, which utilises in-silico techniques such as multitarget chemometric modelling, fragment analysis, virtual screening, molecular docking and dynamics, may provide important guidelines to facilitate the discovery of novel ERK inhibitors.
“…Taken together, six series of chemical fragments are rapidly built from our developed cMAVIs in two steps. These high-quality fragments are demanded in the drug discovery, especially in the fragment-based approaches ( Alen et al., 2019 ; Heightman et al., 2018 ; Kirsch et al., 2019 ). Figure 4 DOS Strategy Applied to Construct Heterocyclic Fragments from 1a and 1a-Alike cMAVIs Note: Unless stated, otherwise R, R 1 , and R 2 stand for H; DCE, 1,2-dichloroethane; NBS, N -bromosuccinimide.…”
Summary
Cross-coupling reactions between aryl iodide and nucleophiles have been well developed. Iodoniums equipped with a reactive C-I(III) bond accelerate cross-coupling reactions of aryl iodide. Among them, cyclic diaryliodoniums are more atom economical; however; they are often in the trap of metal reliance and encounter regioselectivity issues. Now, we have developed a series of highly reactive cyclic monoaryl-vinyl iodoniums that can be tuned to construct C-N, C-O, and C-C bonds without metal catalysis. Under promotion of triethylamine, coupling reactions with aniline, phenol, aromatic acid, and indole proceed rapidly and regioselectively at room temperature. The carbene species is conceptualized as a key intermediate in our mechanism model. Furthermore, the coupling products enable diversity-oriented synthesis strategy to further build up a chemical library of diverse heterocyclic fragments that are in demand in the drug discovery field. Our current work provides a deep insight into the synthetic application of these highly reactive cyclic iodoniums.
“…We performed computational docking analysis of A1541-A1543 compounds against the ERK1/2 protein. A recent study has shown that the ERK1/2 specific inhibitor EQW ( 5-chloranyl-~[12]-(oxan-4-yl)pyrimidin-2-amine, PDB# 6G91) binds pocket B of the kinase [17]. Interestingly, like EQW, Cedrelone was found to occupy pocket B (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Clinical use of these upstream inhibitors often results in drug resistance through amplification of the ERK1/2 gene [21, 22]. To overcome this, Heightman TD et al, recently used a fragment-based library to identify the ERK1/2 inhibitor EQW [17]. While the anti-cancer activity of EQW has not yet been determined, ERK1/2 inhibitor Cedrelone identified in this study binds to similar binding pocket in ERK1/2 as does EQW, resulting in inhibition of the ERK1/2 phosphorylation.…”
Background
MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available.
Method
A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541–43, originally isolated from the plant
Melia azedarach,
exhibiting strong anti-leukemic activity
.
The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia.
Results
Compounds A1541–43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541–43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541–43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541–43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541–43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia.
Conclusions
This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.
Electronic supplementary material
The online version of this article (10.1186/s12885-019-5914-8) contains supplementary material, which is available to authorized users.
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