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1.
Phys Chem Chem Phys ; 21(43): 24147-24164, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31657381

RESUMO

Understanding the selectivity mechanisms of inhibitors towards highly similar proteins is extremely important work on the way to a new drug. Here, we aim to reveal the selectivity mechanisms of type I 1/2 kinase inhibitors towards p21-activated kinase (PAK4) and mitogen-activated protein kinase kinase kinase 14 (MAP3K14, NIK). PAK4, belonging to the serine/threonine protein kinases, is involved in cell signaling pathways and controls cellular functions and has received attention as an attractive drug target. The high sequence identity between PAK4 and NIK makes it challenging to design selective PAK4 inhibitors. In this work, computational methods including protein comparison, molecular docking, QM/MM, molecular dynamics simulations, and density functional theory (DFT) calculation were employed to explore the binding mechanisms of selective inhibitors against NIK and PAK4. The simulation results revealed the crucial factors accounting for selective inhibition of PAK4 over NIK, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. This study will shed light on understanding the selectivity mechanisms of PAK4 and NIK inhibitors.


Assuntos
Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Quinases Ativadas por p21/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Teoria da Densidade Funcional , Humanos , Ligações de Hidrogênio , Camundongos , Análise de Componente Principal , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Alinhamento de Sequência , Eletricidade Estática , Quinases Ativadas por p21/metabolismo
2.
J Chem Theory Comput ; 15(11): 5817-5828, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509413

RESUMO

Molecular dynamics (MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively "scaled" to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled up ligand-water interactions in an attempt to increase the rate of ligand unbinding. After applying our selectively scaled MD (ssMD) approach to several cyclin-dependent kinase-inhibitor complexes, we discovered that we could accelerate ligand unbinding, thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the initial unbinding times (τunbindsim) as well as the accompanying change in free energy (ΔGsim) of the inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers'-based rate extrapolation method and a newly described free energy extrapolation method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.


Assuntos
Quinase 2 Dependente de Ciclina/química , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/metabolismo , Ligantes , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Termodinâmica
3.
Eur J Med Chem ; 178: 232-242, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185413

RESUMO

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-AblWT and Bcr-AblT315I kinases with IC50 of 0.043 µM and 0.17 µM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 µM and 5.42 µM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Mutação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Maleabilidade , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo
4.
Croat Med J ; 60(3): 250-254, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187953

RESUMO

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Dasatinibe/efeitos adversos , Dasatinibe/metabolismo , Síndrome Nefrótica/induzido quimicamente , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Testes Farmacogenômicos , Fenótipo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/uso terapêutico
5.
Drugs ; 79(10): 1037-1051, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161537

RESUMO

Kinase activating missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenically linked to neurodegenerative Parkinson's disease (PD). Over the past decade, substantial effort has been devoted to the development of potent and selective small molecule inhibitors of LRRK2, as well as their preclinical testing across different Parkinson's disease models. This review outlines the genetic and biochemical evidence that pathogenic missense mutations increase LRRK2 kinase activity, which in turn provides the rationale for the development of small molecule inhibitors as potential PD therapeutics. An overview of progress in the development of LRRK2 inhibitors is provided, which in particular indicates that highly selective and potent compounds capable of clinical utility have been developed. We outline evidence from rodent- and human-induced pluripotent stem cell models that support a pathogenic role for LRRK2 kinase activity, and review the substantial experiments aimed at evaluating the safety of LRRK2 inhibitors. We address challenges still to overcome in the translational therapeutic pipeline, including biomarker development and clinical trial strategies, and finally outline the potential utility of LRRK2 inhibitors for other genetic forms of PD and ultimately sporadic PD. Collective evidence supports the ongoing clinical translation of LRRK2 inhibitors as a therapeutic intervention for PD is greatly needed.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Animais , Biomarcadores , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Terapia de Alvo Molecular/métodos , Mutação , Inibidores de Proteínas Quinases/metabolismo , Roedores
6.
Comput Biol Chem ; 80: 324-332, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078911

RESUMO

Various protein kinases are implicated in the pathogenesis of human cervical cancer and many kinase inhibitors have been used to regulate the activity of protein kinases involved in the disease signaling networks. In the present study, a systematic kinase-inhibitor interactome is created for various small-molecule inhibitors across diverse cervical cancer-related kinases by using ontology enrichment, molecular docking, dynamics simulation and energetics analysis. The interactome profile is examined in detail with heatmap analysis and heuristic clustering to derive promising inhibitors that are highly potential to target the kinome of human cervical cancer in a multi-target manner. A number of hit and unhit inhibitors are selected and their cell-suppressing effects are tested against human cervical carcinoma HeLa, from which several inhibitor compounds with high cytotoxicity are successfully identified. A further kinase assay confirms that these inhibitors can generally target their noncognate kinases HER3 and BRaf in cervical cancer with a high or moderate activity; the activity profile are comparable with or even better than that of cognate kinases inhibitors, with IC50 values ranging between 4.8 and 340.6 nM for HER3 and between 37.2 and 638.2 nM for BRaf. This work would help to identify those unexpected kinase-inhibitor interactions in human cervical cancer and to develop new and efficient therapeutic strategy combating the disease.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Neoplasias do Colo do Útero/enzimologia , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ontologia Genética , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/química , Proteínas Quinases/genética , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética
7.
Comput Biol Chem ; 80: 351-363, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31085426

RESUMO

mTOR has become a promising target for many types of cancer like breast, lung and renal cell carcinoma. CoMFA, CoMSIA, Topomer CoMFA and HQSAR were performed on the series of 39 triazine morpholino derivatives. CoMFA analysis showed q2 value of 0.735, r2cv value of 0.722 and r2pred value of 0.769. CoMSIA analysis (SEHD) showed q2 value of 0.761, r2cv value of 0.775 and r2pred value of 0.651. Topomer CoMFA analysis showed q2 value of 0.693, r2 (conventional correlation coefficient) value of 0.940 and r2pred value of 0.720. HQSAR analysis showed q2,r2and r2pred values of 0.694, 0.920 and 0.750, respectively. HQSAR analysis with the combination of atomic number (A), bond type (B) and atomic connections showed q2 and r2 values of 0.655 and 0.891, respectively. Contour maps from all studies provided significant insights. Molecular docking studies with molecular dynamics simulations were carried out on the highly potent compound 36. Furthermore, four acridine derivatives were designed and docking results of these designed compounds showed the same interactions as that of the standard PI-103 which proved the efficiency of 3D-QSAR and MD/MS study. In future, this study might be useful prior to synthesis for the designing of novel mTOR inhibitors.


Assuntos
Morfolinas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazinas/metabolismo , Acridinas/química , Acridinas/metabolismo , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Conjuntos de Dados como Assunto , Desenho de Drogas , Humanos , Ligações de Hidrogênio , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfolinas/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Serina-Treonina Quinases TOR/química , Triazinas/química
8.
Comput Biol Chem ; 80: 374-383, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31103918

RESUMO

Colony-stimulating factor 1 receptor is a type III receptor protein tyrosine kinase belonging to PDGFR family. CSF1R signaling is essential for differentiation, proliferation and survival of macrophages. Aberrant expression of CSF1R appears to be an attractive target in several cancer types. Higher expression of CSF1R ligands correlates to tumor progression. CSF1R inhibitors have been shown to suppress cancers. We have attempted an in silico fragment derived drug discovery approach by screening ˜25,000 in-house compounds as potential CSF1R inhibitors. Using FBDD approach we have identified six diverse fragments that exhibit affinity towards hinge region of CSF1R. Some of the fragments 5-nitroindole and 7-azaindole and their derivatives were synthesized for further evaluation. The in silico and in vitro enzyme activity studies reveal moderate inhibition of CSF1R kinase activity by 5-nitroindole and good inhibition by 7-azaindole fragments. Bio and chemiinformatics studies have shown that 7-azaindole compounds have better membrane permeability and enzyme inhibition properties. Molecular docking studies show that the amino acid residues 664-666 in the hinge region of the cytosolic domain of CSF1R to be the preferred region of binding for nitroindole and azaindole derivatives. Further optimization and biological analysis would identify these fragments as potential and promising leads as CSF1R inhibitors.


Assuntos
Indóis/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Biologia Computacional , Desenho de Drogas , Humanos , Indóis/síntese química , Indóis/química , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/química , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo
9.
Comput Biol Chem ; 80: 79-89, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928871

RESUMO

The current study was set to discover selective Plasmodium falciparum phosphatidylinositol-4-OH kinase type III beta (pfPI4KB) inhibitors as potential antimalarial agents using combined structure-based and ligand-based drug discovery approach. A comparative model of pfPI4KB was first constructed and validated using molecular docking techniques. Performance of Autodock4.2 and Vina4 software in predicting the inhibitor-PI4KB binding mode and energy was assessed based on two Test Sets: Test Set I contained five ligands with resolved crystal structures with PI4KB, while Test Set II considered eleven compounds with known IC50 value towards PI4KB. The outperformance of Autodock as compared to Vina was reported, giving a correlation coefficient (R2) value of 0.87 and 0.90 for Test Set I and Test Set II, respectively. Pharmacophore-based screening was then conducted to identify drug-like molecules from ZINC database with physicochemical similarity to two potent pfPI4KB inhibitors -namely cpa and cpb. For each query inhibitor, the best 1000 hits in terms of TanimotoCombo scores were selected and subjected to molecular docking and molecular dynamics (MD) calculations. Binding energy was then estimated using molecular mechanics-generalized Born surface area (MM-GBSA) approach over 50 ns MD simulations of the inhibitor-pfPI4KB complexes. According to the calculated MM-GBSA binding energies, ZINC78988474 and ZINC20564116 were identified as potent pfPI4KB inhibitors with binding energies better than those of cpa and cpb, with ΔGbinding ≥ -34.56 kcal/mol. The inhibitor-pfPI4KB interaction and stability were examined over 50 ns MD simulation; as well the selectivity of the identified inhibitors towards pfPI4KB over PI4KB was reported.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , 1-Fosfatidilinositol 4-Quinase/metabolismo , Antimaláricos/metabolismo , Plasmodium falciparum/enzimologia , Inibidores de Proteínas Quinases/metabolismo , 1-Fosfatidilinositol 4-Quinase/química , Sequência de Aminoácidos , Antimaláricos/química , Domínio Catalítico , Bases de Dados de Compostos Químicos/estatística & dados numéricos , Descoberta de Drogas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Alinhamento de Sequência
10.
Chemistry ; 25(27): 6831-6839, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31026091

RESUMO

Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3 -rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.


Assuntos
Aurora Quinase A/metabolismo , Desenho de Drogas , Inibidores de Proteínas Quinases/síntese química , Regulação Alostérica , Aurora Quinase A/antagonistas & inibidores , Sítios de Ligação , Cristalografia por Raios X , Bases de Dados de Compostos Químicos , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína
11.
Gene ; 698: 120-128, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30849534

RESUMO

Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to the extracellular stimulators. Hyperactivation of PI3K signalling cascades is one among the most ordinary events in human cancers. Focusing on the PI3K pathway remains both a chance and a challenge for cancer therapy. The high recurrence of phosphoinositide 3-kinase (PI3K) pathway adjustments in cancer has led to a surge in the progression of PI3K inhibitors. Recent developments incorporate a re-assessment of the oncogenic mechanisms behind PI3K pathway modifications. Receptor tyrosine kinases upstream of PI3K, the p110a catalytic fractional unit of PI3K, the downstream kinase, AKT, and therefore the negative regulator, PTEN, are all often altered in cancer. In this review, we consider about the phosphoinositide 3-kinases family and mechanisms of PI3K-Akt stimulation in cancer.


Assuntos
Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Recidiva Local de Neoplasia/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia
12.
Phys Chem Chem Phys ; 21(14): 7544-7558, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30895980

RESUMO

The proviral integration site of the Moloney leukemia virus (PIM) family includes three homologous members. PIM-1 kinase is an important target in effective therapeutic interventions of lymphomas, prostate cancer and leukemia. In the current work, we performed free energy calculations to calculate the binding affinities of several inhibitors targeting this protein. The alchemical method with integration and perturbation-based estimators and the end-point methods were compared. The computational results indicated that the alchemical method can accurately predict the binding affinities, while the end-point methods give relatively unreliable predictions. Decomposing the free energy difference into enthalpic and entropic components with MBAR reweighting enabled us to investigate the detailed thermodynamic parameters with which the entropy-enthalpy compensation in this protein-ligand binding case is identified. We then studied the conformational ensemble, and the important protein-ligand interactions were identified. The current work sheds light on the understanding of the PIM-1-kinase-inhibitor interactions at the atomic level and will be useful in the further development of potential drugs.


Assuntos
Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Sítios de Ligação , Humanos , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Teoria Quântica , Termodinâmica
13.
PLoS Pathog ; 15(3): e1007601, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30883607

RESUMO

Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interfering RNA (siRNA) loss-of-function screen of IV replication in A549 cells. Analysis of four different IV strains including a highly pathogenic avian H5N1 strain, an influenza B virus (IBV) and two human influenza A viruses (IAVs) revealed 133 genes required by all four IV strains. According to gene enrichment analyses, these strain-independent host genes were particularly enriched for nucleocytoplasmic trafficking. In addition, 360 strain-specific genes were identified with distinct patterns of usage for IAVs versus IBV and human versus avian IVs. The strain-independent host genes served to define 43 experimental and otherwise clinically approved drugs, targeting reportedly fourteen of the encoded host factors. Amongst the approved drugs, the urea-based kinase inhibitors (UBKIs) regorafenib and sorafenib exhibited a superior therapeutic window of high IV antiviral activity and low cytotoxicity. Both UBKIs appeared to block a cell signaling pathway involved in IV replication after internalization, yet prior to vRNP uncoating. Interestingly, both compounds were active also against unrelated viruses including cowpox virus (CPXV), hantavirus (HTV), herpes simplex virus 1 (HSV1) and vesicular stomatitis virus (VSV) and showed antiviral efficacy in human primary respiratory cells. An in vitro resistance development analysis for regorafenib failed to detect IV resistance development against this drug. Taken together, the otherwise clinically approved UBKIs regorafenib and sorafenib possess high and broad-spectrum antiviral activity along with substantial robustness against resistance development and thus constitute attractive host-directed drug candidates against a range of viral infections including influenza.


Assuntos
Orthomyxoviridae/genética , Orthomyxoviridae/imunologia , Replicação Viral/fisiologia , Células A549 , Transporte Ativo do Núcleo Celular/fisiologia , Antivirais , Interações Hospedeiro-Patógeno , Humanos , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/imunologia , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vírus da Influenza B/genética , Vírus da Influenza B/imunologia , Influenza Humana , Orthomyxoviridae/patogenicidade , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/metabolismo , Piridinas/farmacologia , Interferência de RNA/imunologia , Vírus de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Sorafenibe/farmacologia , Ureia/metabolismo
14.
Med Chem ; 15(6): 588-601, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799792

RESUMO

BACKGROUND: PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. METHODS: Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). RESULTS: The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. CONCLUSION: Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.


Assuntos
Descoberta de Drogas , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Ligantes , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosfatidilinositol 3-Quinases/química , Ligação Proteica , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade
15.
Eur J Pharmacol ; 850: 126-134, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753868

RESUMO

Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC50 = 10 ±â€¯3.1 and 7.8 ±â€¯0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC50 = 51.7 ±â€¯9.1 nM) as well as in aortic rings (IC50 = 45.5 ±â€¯1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (>400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Antagonistas dos Receptores de Endotelina/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Ratos , Distribuição Tecidual , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases Associadas a rho/química , Quinases Associadas a rho/metabolismo
16.
Eur J Med Chem ; 166: 304-317, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30731399

RESUMO

Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design.


Assuntos
Desenho de Drogas , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Quinazolinas/química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
17.
Mar Drugs ; 17(2)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699889

RESUMO

The recent success of small-molecule kinase inhibitors as anticancer drugs has generated significant interest in their application to other clinical areas, such as disorders of the central nervous system (CNS). However, most kinase inhibitor drug candidates investigated to date have been ineffective at treating CNS disorders, mainly due to poor blood⁻brain barrier (BBB) permeability. It is, therefore, imperative to evaluate new chemical entities for both kinase inhibition and BBB permeability. Over the last 35 years, marine biodiscovery has yielded 471 natural products reported as kinase inhibitors, yet very few have been evaluated for BBB permeability. In this study, we revisited these marine natural products and predicted their ability to cross the BBB by applying freely available open-source chemoinformatics and machine learning algorithms to a training set of 332 previously reported CNS-penetrant small molecules. We evaluated several regression and classification models, and found that our optimised classifiers (random forest, gradient boosting, and logistic regression) outperformed other models, with overall cross-validated model accuracies of 80%⁻82% and 78%⁻80% on external testing. All 3 binary classifiers predicted 13 marine-derived kinase inhibitors with appropriate physicochemical characteristics for BBB permeability.


Assuntos
Produtos Biológicos/farmacologia , Barreira Hematoencefálica/fisiologia , Inibidores de Proteínas Quinases/metabolismo , Animais , Organismos Aquáticos/química , Produtos Biológicos/química , Produtos Biológicos/farmacocinética , Transporte Biológico , Simulação por Computador , Humanos , Doenças Neurodegenerativas , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
18.
J Med Chem ; 62(2): 575-588, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30623649

RESUMO

Pyruvate dehydrogenase kinase 4 (PDK4) activation is associated with metabolic diseases including hyperglycemia, insulin resistance, allergies, and cancer. Structural modifications of hit anthraquinone led to the identification of a new series of allosteric PDK4 inhibitors. Among this series, compound 8c showed promising in vitro activity with an IC50 value of 84 nM. Good metabolic stability, pharmacokinetic profiles, and possible metabolites were suggested. Compound 8c improved glucose tolerance in diet-induced obese mice and ameliorated allergic reactions in a passive cutaneous anaphylaxis mouse model. Additionally, compound 8c exhibited anticancer activity by controlling cell proliferation, transformation, and apoptosis. From the molecular docking studies, compound 8c displayed optimal fitting in the lipoamide binding site (allosteric) with a full fitness, providing a new scaffold for drug development toward PDK4 inhibitors.


Assuntos
Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Administração Oral , Animais , Antraquinonas/química , Antraquinonas/metabolismo , Antraquinonas/uso terapêutico , Sítios de Ligação , Linhagem Celular , Meia-Vida , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Masculino , Doenças Metabólicas/patologia , Doenças Metabólicas/veterinária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/patologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Ratos , Relação Estrutura-Atividade
19.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669433

RESUMO

A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, α -epoxyarglabin, cytisinyl epoxyarglabin, 1 ß ,10 α -epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04⁻5.3 Å for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an α -methylene- γ -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.


Assuntos
Glutationa/metabolismo , Lactonas/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Sesquiterpenos/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo , Comunicação Celular , Humanos , Células Jurkat , Lactonas/síntese química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Sesquiterpenos/síntese química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Drug Saf ; 42(2): 159-179, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649744

RESUMO

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Gastrointestinais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores da Angiogênese/metabolismo , Animais , Antineoplásicos/metabolismo , Desenvolvimento de Medicamentos/métodos , Neoplasias Gastrointestinais/metabolismo , Humanos , Neovascularização Patológica/metabolismo , Ligação Proteica/fisiologia , Inibidores de Proteínas Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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