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1.
Front Biosci (Landmark Ed) ; 27(5): 167, 2022 05 23.
Article En | MEDLINE | ID: mdl-35638434

The mitogen-activated protein kinase (MAPK) pathways are ubiquitous in cellular signaling and are essential for proper biological functions. Disruptions in this signaling axis can lead to diseases such as the development of cancer. In this review, we discuss members of the MAP3K family and correlate their mRNA expression levels to patient survival outcomes in different cancers. Furthermore, we highlight the importance of studying the MAP3K family due to their important roles in the larger, overall MAPK pathway, relationships with cancer progression, and the understudied status of these kinases.


MAP Kinase Signaling System , Neoplasms , Humans , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Neoplasms/genetics , Phosphorylation , Signal Transduction/genetics
2.
Acta Crystallogr E Crystallogr Commun ; 78(Pt 5): 485-489, 2022 May 01.
Article En | MEDLINE | ID: mdl-35547791

The title compound, C10H13BrN2O3S, 1, contains a sulfonyl urea moiety, which possesses potential therapeutic functions (e.g., anti-diabetic and herbicidal). The geometry of 1 is similar to its closely related analogues, chlorpropamide and tolbutamide. This compound crystallizes in the monoclinic space group C2/c, having one mol-ecule in its asymmetric unit. The crystal structure of 1, recorded at 296 K, shows inter-molecular N-H⋯O and C-H⋯O-type infinite hydrogen-bonded chains involving the sulfonyl urea moiety. Hirshfeld surface analysis and the two-dimensional fingerprint plots confirmed hydrogen bonding as the dominant feature in the crystal packing.

3.
Acta Crystallogr E Crystallogr Commun ; 77(Pt 4): 360-365, 2021 Apr 01.
Article En | MEDLINE | ID: mdl-33936758

The title sterically congested piperazine derivative, C20H27FN2O2, was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an N-tert-butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitro-gen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is sp 3 hybridized while the other is sp 2 hybridized. Inter-molecular inter-actions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogen-bond-like inter-actions (C-H⋯O) and C-H⋯π inter-actions with the dispersion inter-actions as the major source of attraction are present in the crystal packing.

4.
Oncoscience ; 8: 64-71, 2021.
Article En | MEDLINE | ID: mdl-34026925

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study, we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC.

5.
J Cell Biochem ; 122(8): 835-850, 2021 08.
Article En | MEDLINE | ID: mdl-33876843

Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.


Cell Movement , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , MAP Kinase Kinase 5/metabolism , MAP Kinase Signaling System , Proto-Oncogene Proteins c-fos/biosynthesis , Triple Negative Breast Neoplasms/metabolism , Female , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/genetics , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/genetics , MAP Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase 5/genetics , MCF-7 Cells , Proto-Oncogene Proteins c-fos/genetics , Triple Negative Breast Neoplasms/genetics
6.
Transl Oncol ; 14(6): 101046, 2021 Jun.
Article En | MEDLINE | ID: mdl-33761370

The epithelial to mesenchymal transition (EMT) is characterized by a loss of cell polarity, a decrease in the epithelial cell marker E-cadherin, and an increase in mesenchymal markers including the zinc-finger E-box binding homeobox (ZEB1). The EMT is also associated with an increase in cell migration and anchorage-independent growth. Induction of a reversal of the EMT, a mesenchymal to epithelial transition (MET), is an emerging strategy being explored to attenuate the metastatic potential of aggressive cancer types, such as triple-negative breast cancers (TNBCs) and tamoxifen-resistant (TAMR) ER-positive breast cancers, which have a mesenchymal phenotype. Patients with these aggressive cancers have poor prognoses, quick relapse, and resistance to most chemotherapeutic drugs. Overexpression of extracellular signal-regulated kinase (ERK) 1/2 and ERK5 is associated with poor patient survival in breast cancer. Moreover, TNBC and tamoxifen resistant cancers are unresponsive to most targeted clinical therapies and there is a dire need for alternative therapies. In the current study, we found that MAPK3, MAPK1, and MAPK7 gene expression correlated with EMT markers and poor overall survival in breast cancer patients using publicly available datasets. The effect of ERK1/2 and ERK5 pathway inhibition on MET was evaluated in MDA-MB-231, BT-549 TNBC cells, and tamoxifen-resistant MCF-7 breast cancer cells. Moreover, TU-BcX-4IC patient-derived primary TNBC cells were included to enhance the translational relevance of our study. We evaluated the effect of pharmacological inhibitors and lentivirus-induced activation or inhibition of the MEK1/2-ERK1/2 and MEK5-ERK5 pathways on cell morphology, E-cadherin, vimentin and ZEB1 expression. Additionally, the effects of pharmacological inhibition of trametinib and XMD8-92 on nuclear localization of ERK1/2 and ERK5, cell migration, proliferation, and spheroid formation were evaluated. Novel compounds that target the MEK1/2 and MEK5 pathways were used in combination with the AKT inhibitor ipatasertib to understand cell-specific responses to kinase inhibition. The results from this study will aid in the design of innovative therapeutic strategies that target cancer metastases.

7.
Biomolecules ; 11(2)2021 01 29.
Article En | MEDLINE | ID: mdl-33572742

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-ß (TGF-ß), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and ß-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.


Epithelial-Mesenchymal Transition , Mitogen-Activated Protein Kinase 7/metabolism , Mutation , Neoplasms/metabolism , Animals , Cell Adhesion , Cytoskeleton/metabolism , Disease Progression , Extracellular Matrix/metabolism , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplastic Stem Cells/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Tumor Microenvironment , Tumor Necrosis Factor-alpha/metabolism
8.
Front Oncol ; 10: 1164, 2020.
Article En | MEDLINE | ID: mdl-32850332

Conventional mitogen-activated protein kinase (MAPK) family members regulate diverse cellular processes involved in tumor initiation and progression, yet the role of ERK5 in cancer biology is not fully understood. Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. ERK5 signaling contributes to drug resistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT). More recently a role for ERK5 in regulation of the extracellular matrix (ECM) has been proposed, and here we investigated the necessity of ERK5 in TNBC tumor formation. Depletion of ERK5 expression using the CRISPR/Cas9 system in MDA-MB-231 and Hs-578T cells resulted in loss of mesenchymal features, as observed through gene expression profile and cell morphology, and suppressed TNBC cell migration. In vivo xenograft experiments revealed ERK5 knockout disrupted tumor growth kinetics, which was restored using high concentration Matrigel™ and ERK5-ko reduced expression of the angiogenesis marker CD31. These findings implicated a role for ERK5 in the extracellular matrix (ECM) and matrix integrity. RNA-sequencing analyses demonstrated downregulation of matrix-associated genes, integrins, and pro-angiogenic factors in ERK5-ko cells. Tissue decellularization combined with cryo-SEM and interrogation of biomechanical properties revealed that ERK5-ko resulted in loss of key ECM fiber alignment and mechanosensing capabilities in breast cancer xenografts compared to parental wild-type cells. In this study, we identified a novel role for ERK5 in tumor growth kinetics through modulation of the ECM and angiogenesis axis in breast cancer.

9.
J Cell Biochem ; 121(2): 1156-1168, 2020 02.
Article En | MEDLINE | ID: mdl-31464004

Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.


Cell Survival/drug effects , MAP Kinase Kinase 5/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Triple Negative Breast Neoplasms/metabolism , Apoptosis/drug effects , Benzodiazepinones/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Synergism , Female , Humans , MAP Kinase Kinase 5/antagonists & inhibitors , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Piperazines/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyridones/pharmacology , Pyrimidines/pharmacology , Pyrimidinones/pharmacology
10.
Front Oncol ; 9: 672, 2019.
Article En | MEDLINE | ID: mdl-31417863

Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound 1 from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound 1 decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells.

12.
Mol Pharmacol ; 92(5): 564-575, 2017 11.
Article En | MEDLINE | ID: mdl-28830914

N-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here, we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione. Furthermore, glutathione depletion failed to attenuate the protective effects of NAC. MG132 elicited a robust increase in the folding chaperone heat shock protein 70 (Hsp70), and NAC mitigated this effect. Nevertheless, three independent inhibitors of Hsp70 function ablated the protective effects of NAC, suggesting that NAC may help preserve Hsp70 chaperone activity and improve protein quality control without need for Hsp70 induction. Consistent with this view, NAC abolished an increase in ubiquitinated proteins in MG132-treated astrocytes. However, NAC did not affect the loss of proteasome activity in response to MG132, demonstrating that it boosted protein homeostasis and cell viability without directly interfering with the efficacy of this proteasome inhibitor. The thiol-containing molecules l-cysteine and d-cysteine both mimicked the protective effects of NAC, whereas the thiol-lacking molecule N-acetyl-S-methyl-l-cysteine failed to exert protection or blunt the rise in ubiquitinated proteins. Collectively, these findings suggest that the thiol group in NAC is required for its effects on glial viability and protein quality control.


Acetylcysteine/pharmacology , Astrocytes/drug effects , Cytoprotection/drug effects , Glutathione , Protein Folding/drug effects , Animals , Astrocytes/physiology , Cell Survival/drug effects , Cell Survival/physiology , Cytoprotection/physiology , Dose-Response Relationship, Drug , Female , HSP70 Heat-Shock Proteins/antagonists & inhibitors , HSP70 Heat-Shock Proteins/physiology , Leupeptins/toxicity , Male , Rats , Rats, Sprague-Dawley
13.
Cancer Lett ; 392: 51-59, 2017 04 28.
Article En | MEDLINE | ID: mdl-28153789

Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents.


MAP Kinase Kinase 5/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Neoplasms/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction , Animals , Antineoplastic Agents/therapeutic use , Apoptosis , Cell Differentiation , Cell Proliferation , Drug Resistance, Neoplasm , Humans , MAP Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase 5/genetics , Molecular Targeted Therapy , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/genetics , Signal Transduction/drug effects
14.
Curr Pharm Des ; 18(9): 1199-216, 2012.
Article En | MEDLINE | ID: mdl-22316150

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.


Anti-HIV Agents/pharmacology , Computer-Aided Design , HIV Infections/drug therapy , Anti-HIV Agents/administration & dosage , Cyclophilin A/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Delivery Systems , Drug Design , HIV Infections/virology , HIV-1/drug effects , Humans , Molecular Dynamics Simulation , Monte Carlo Method
15.
Bioorg Med Chem Lett ; 21(16): 4836-43, 2011 Aug 15.
Article En | MEDLINE | ID: mdl-21741239

Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.


Antihypertensive Agents/pharmacology , Enzyme Inhibitors/pharmacology , Phenyl Ethers/pharmacology , Renin/antagonists & inhibitors , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A Inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Hypertension/drug therapy , Models, Molecular , Molecular Conformation , Phenyl Ethers/chemical synthesis , Phenyl Ethers/chemistry , Rats , Rats, Transgenic , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/isolation & purification , Stereoisomerism , Structure-Activity Relationship
16.
Bioorg Med Chem ; 19(1): 359-73, 2011 Jan 01.
Article En | MEDLINE | ID: mdl-21144757

Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive and behavioral impairment. The two classic pathological hallmarks of AD include extraneuronal deposition of amyloid ß (Aß) and intraneuronal formation of neurofibrillary tangles (NFTs). NFTs contain hyperphosphorylated tau. Tau is the major microtubule-associated protein in neurons and stabilizes microtubules (MTs). Cyclin dependent kinase 5 (CDK5), when activated by the regulatory binding protein p25, phosphorylates tau at a number of proline-directed serine/threonine residues, resulting in formation of phosphorylated tau as paired helical filaments (PHFs) then in subsequent deposition of PHFs as NFTs. Beginning with the structure of Roscovitine, a moderately selective CDK5 inhibitor, we sought to conduct structural modifications to increase inhibitory potency of CDK5 and increase selectivity over a similar enzyme, cyclin dependent kinase 2 (CDK2). The design, synthesis, and testing of a series of 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles is presented.


Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Cyclin-Dependent Kinase 5/antagonists & inhibitors , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Benzimidazoles/chemistry , Models, Molecular , Protein Kinase Inhibitors/chemistry
17.
Bioorg Med Chem ; 18(22): 8054-60, 2010 Nov 15.
Article En | MEDLINE | ID: mdl-20965737

In a prior communication we identified a novel class of benzimidazole-based inhibitors of EGF-induced phosphorylation of ERK5. In this paper we examine the biological activity of several 1-isopropyl-4-amino-6-ether linked benzimidazole-based compounds for their ability to selectively inhibit EGF-mediated ERK5 phosphorylation; potential utility of variation at the 6-position was indicated by the initial structural feature survey. Modification of EGF-induced formation of pERK1/2 and pERK5 in HEK293 cells were analyzed by Western blot analysis. Subsequent analysis of selected compounds in a high-throughput multiple kinase scan and the NCI 60-cell-line screen is presented.


Benzimidazoles/chemistry , Mitogen-Activated Protein Kinase 7/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Epidermal Growth Factor/metabolism , HEK293 Cells , Humans , Mitogen-Activated Protein Kinase 7/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Structure-Activity Relationship
18.
Bioorg Med Chem Lett ; 20(9): 2892-6, 2010 May 01.
Article En | MEDLINE | ID: mdl-20382528

The MEK-signaling pathways are complex but critical signaling cascades that correlate an extracellular signaling event with internal cell processes. To date at least seven MEK isozymes have been identified. MEK5, in particular, is upregulated in multiple forms of tumors. Analysis of the EGF-induced MEK5 signaling cascade in cultured HEK cells has identified compounds that can inhibit MEK5 phosphorylation of ERK5; observed biological activity is dependent on chemical variation.


Benzimidazoles/chemistry , MAP Kinase Kinase 5/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Signal Transduction/drug effects , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Cell Line , Epidermal Growth Factor/pharmacology , Humans , MAP Kinase Kinase 5/metabolism , Mitogen-Activated Protein Kinase 7/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology
19.
Bioorg Med Chem Lett ; 20(2): 694-9, 2010 Jan 15.
Article En | MEDLINE | ID: mdl-19959358

Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.


Amines/chemistry , Carbamates/chemistry , Enzyme Inhibitors/chemistry , Piperidines/chemistry , Renin/antagonists & inhibitors , Administration, Oral , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Binding Sites , Blood Pressure/drug effects , Carbamates/chemical synthesis , Carbamates/pharmacokinetics , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Haplorhini , Humans , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Transgenic , Renin/blood , Renin/metabolism , Structure-Activity Relationship
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