RESUMO
Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.
Assuntos
Interleucina-2 , Receptores de Antígenos de Linfócitos T , Camundongos , Animais , Chlorocebus aethiops , Proteínas Serina-Treonina Quinases , Células COSRESUMO
Toll-like receptor (TLR) 7 and TLR8 are transmembrane receptors that recognize single-stranded RNA. Activation of these receptors results in immune cell stimulation and inflammatory cytokine production, which is normally a protective host response. However, aberrant activation of TLR7/8 is potentially pathogenic and linked to progression of certain autoimmune diseases such as lupus. Thus, we hypothesize that an inhibitor that blocks TLR7/8 would be an effective therapeutic treatment. Prior efforts to develop inhibitors of TLR7/8 have been largely unsuccessful as a result of the challenge of producing a small-molecule inhibitor for these difficult targets. Here, we report the characterization of M5049 and compound 2, molecules which were discovered in a medicinal chemistry campaign to produce dual TLR7/8 inhibitors with drug-like properties. Both compounds showed potent and selective activity in a range of cellular assays for inhibition of TLR7/8 and block synthetic ligands and natural endogenous RNA ligands such as microRNA and Alu RNA. M5049 was found to be potent in vivo as TLR7/8 inhibition efficaciously treated disease in several murine lupus models and, interestingly, was efficacious in a disease context in which TLR7/8 activity has not previously been considered a primary disease driver. Furthermore, M5049 had greater potency in disease models than expected based on its in vitro potency and pharmacokinetic/pharmacodynamic properties. Because of its preferential accumulation in tissues, and ability to block multiple TLR7/8 RNA ligands, M5049 may be efficacious in treating autoimmunity and has the potential to provide benefit to a variety of patients with varying disease pathogenesis. SIGNIFICANCE STATEMENT: This study reports discovery of a novel toll-like receptor (TLR) 7 and TLR8 inhibitor (M5049); characterizes its binding mode, potency/selectivity, and pharmacokinetic and pharmacodynamic properties; and demonstrates its potential for treating autoimmune diseases in two mouse lupus models. TLR7/8 inhibition is unique in that it may block both innate and adaptive autoimmunity; thus, this study suggests that M5049 has the potential to benefit patients with autoimmune diseases.
Assuntos
Autoimunidade/efeitos dos fármacos , Descoberta de Drogas , Receptor 7 Toll-Like/antagonistas & inibidores , Receptor 8 Toll-Like/antagonistas & inibidores , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Proteica , Receptor 7 Toll-Like/química , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/química , Receptor 8 Toll-Like/metabolismoRESUMO
Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 µM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Mamárias Animais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Sob a Curva , Cães , Feminino , Meia-Vida , Haplorrinos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Imidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.
Assuntos
Descoberta de Drogas , Ligantes , Estudos Prospectivos , Estudos Retrospectivos , TermodinâmicaRESUMO
Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.
Assuntos
Ciclofilinas/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Lactamas/farmacologia , Cristalografia por Raios X , Ciclofilinas/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (Btk) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage (e.g. B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible Btk inhibitors targeting Cys481 within the ATP-binding pocket have been applied in the treatment of B-cell malignancies. Starting from a fragment, we discovered a novel series of potent covalent irreversible Btk inhibitors that bear N-linked groups occupying the solvent accessible pocket (SAP) of the active site of the Btk kinase domain. The hit molecules, however, displayed high P-gp mediated efflux ratio (ER) and poor A-B permeability in Caco-2 assay. By decreasing tPSA, installing steric hindrance and adjusting clogP, one top molecule 9 was discovered, which showed a 99% decrease in efflux ratio and a 90-fold increase in A-B permeability compared to hit molecule 1.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Niacinamida/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/química , Animais , Células CACO-2 , Domínio Catalítico , Humanos , Camundongos , Estrutura Molecular , Niacinamida/análogos & derivados , Niacinamida/síntese química , Niacinamida/farmacocinética , Permeabilidade , Piperidinas , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacologiaRESUMO
Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Adenina/análogos & derivados , Administração Oral , Animais , Células CACO-2 , Humanos , Camundongos , Estrutura Molecular , Piperidinas , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/farmacologia , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/química , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B-cell receptor (BCR), Fc receptors (FcRs), and toll-like receptors. It has become an attractive drug target because its inhibition may provide significant efficacy by simultaneously blocking multiple disease mechanisms. Consequently, a large number of Btk inhibitors have been developed. These compounds have diverse binding modes, and both reversible and irreversible inhibitors have been developed. Reported herein, we have tested nine Btk inhibitors and characterized on a molecular level how their interactions with Btk define their ability to block different signaling pathways. By solving the crystal structures of Btk inhibitors bound to the enzyme, we discovered that the compounds can be classified by their ability to trigger sequestration of Btk residue Y551. In cells, we found that sequestration of Y551 renders it inaccessible for phosphorylation. The ability to sequester Y551 was an important determinant of potency against FcεR signaling as Y551 sequestering compounds were more potent for inhibiting basophils and mast cells. This result was true for the inhibition of FcγR signaling as well. In contrast, Y551 sequestration was less a factor in determining potency against BCR signaling. We also found that Btk activity is regulated differentially in basophils and B cells. These results elucidate important determinants for Btk inhibitor potency against different signaling pathways and provide insight for designing new compounds with a broader inhibitory profile that will likely result in greater efficacy.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores Fc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tirosina/metabolismo , Tirosina Quinase da Agamaglobulinemia , Linhagem Celular Tumoral , Análise por Conglomerados , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Humanos , Modelos Moleculares , Proteínas Mutantes/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismoRESUMO
This article presents the design, implementation, and outcomes of a certification preparation program for nurses working in an outpatient clinic. A nurse educator designed curriculum using the Certified Breast Care Nurse test blueprint. Nurse administrators provided the resources and the staff coverage to allow all staff members to attend the sessions without disruption to patient care. This outpatient center has achieved and sustained 100% certification among eligible nurses over the past 5 years.
Assuntos
Assistência Ambulatorial/normas , Neoplasias da Mama/enfermagem , Institutos de Câncer/normas , Enfermagem Oncológica/educação , Garantia da Qualidade dos Cuidados de Saúde/normas , Assistência Ambulatorial/métodos , Assistência Ambulatorial/organização & administração , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Institutos de Câncer/organização & administração , Certificação/métodos , Certificação/normas , Educação Continuada em Enfermagem/métodos , Educação Continuada em Enfermagem/organização & administração , Educação Continuada em Enfermagem/normas , Avaliação Educacional/métodos , Avaliação Educacional/normas , Feminino , Humanos , Satisfação no Emprego , Modelos Educacionais , Enfermagem Oncológica/normas , Educação de Pacientes como Assunto/métodos , Educação de Pacientes como Assunto/normas , Avaliação de Programas e Projetos de Saúde , Garantia da Qualidade dos Cuidados de Saúde/métodos , Desenvolvimento de Pessoal/métodos , Desenvolvimento de Pessoal/organização & administração , Desenvolvimento de Pessoal/normas , Recursos HumanosRESUMO
Patients undergoing total laryngectomy face the challenge of an altered anatomy with the resultant changes in quality of life and significant requirements for post-operative care. Increased production of secretions and sputum, the need for ongoing suctioning, and the formation of stomal crusting require meticulous post-operative care. The use of Heat and Moisture Exchange (HME) devices has been shown to decrease the effect of these factors. This article describes the nature of these devices and their use. The literature is reviewed regarding the long term benefits and new data are presented suggesting an immediate post-operative benefit as well. Finally, costs and other considerations for successful use of HME devices are presented.
Assuntos
Laringectomia/reabilitação , Terapia Respiratória/instrumentação , Temperatura Alta , Humanos , Umidade , Testes de Função Respiratória , Fenômenos Fisiológicos RespiratóriosRESUMO
BACKGROUND: Chronic shoulder pain is a common presenting compliant in general practice. The differential diagnosis is broad and varies with patient age. OBJECTIVE: This article reviews the management of patients presenting with chronic shoulder pain. A structured approach to history and physical examination is presented, and appropriate investigations are discussed. Non-surgical and surgical treatment options are reviewed. DISCUSSION: Many patients presenting with chronic shoulder pain can be successfully treated non-surgically. A multidisciplinary approach including physiotherapy, occupational therapy and psychology as needed will optimise care. Patients presenting with acute injuries or 'red flag' diagnoses should be urgently referred for specialist care. Referral to an orthopaedic surgeon is also recommended for patients who have failed an appropriate course of non-surgical treatment.
Assuntos
Medicina Geral , Dor de Ombro , Humanos , Dor de Ombro/diagnóstico , Dor de Ombro/etiologia , Dor de Ombro/terapia , Modalidades de Fisioterapia , Medicina de Família e Comunidade , Exame FísicoRESUMO
COVID-19 readmissions are associated with increased patient mortality and healthcare system strain. This retrospective cohort study of PCR-confirmed COVID-19 positive adults (>18 years) hospitalized and readmitted within 30 days of discharge from index admission was performed at eight Atlanta hospitals from March to December 2020. The objective was to describe COVID-19 patient-level demographics and clinical characteristics, and community-level social determinants of health (SDoH) that contribute to 30-day readmissions. Demographics, comorbidities, COVID-19 treatment, and discharge disposition data were extracted from the index admission. ZIP codes were linked to a demographic/lifestyle database interpolating to community-level SDoH. Of 7155 patients with COVID-19, 463 (6.5%) had 30-day, unplanned, all-cause hospital readmissions. Statistically significant differences were not found in readmissions stratified by age, sex, race, or ethnicity. Patients with a high-risk Charlson Comorbidity Index had higher odds of readmission (OR 4.8 (95% CI: 2.1 to 11.0)). Remdesivir treatment and intensive care unit (ICU) care were associated with lower odds of readmission (OR 0.5 (95% CI: 0.4 to 0.8) and OR 0.5 (95% CI: 0.4 to 0.7), respectively). Patients residing in communities with larger average household size were less likely to be readmitted (OR 0.7 (95% CI: 0.5 to 0.9). In this cohort, patients who received remdesivir, were cared for in an ICU, and resided in ZIP codes with higher proportions of residents with increased social support had lower odds of readmission. These patient-level factors and community-level SDoH may be used to identify patients with COVID-19 who are at increased risk of readmission.
Assuntos
Tratamento Farmacológico da COVID-19 , Readmissão do Paciente , Adulto , Hospitais , Humanos , Estudos Retrospectivos , Fatores de Risco , Determinantes Sociais da SaúdeRESUMO
For oligonucleotide-based therapeutics, a thorough understanding of the thermodynamic properties of duplex formation is critical to developing stable and potent drugs. For unmodified small interfering RNA (siRNA), DNA antisense oligonucleotide (AON) and locked nucleic acid (LNA), DNA/LNA modified oligonucleotides, nearest neighbor (NN) methods can be effectively used to quickly and accurately predict duplex thermodynamic properties such as melting point. Unfortunately, for chemically modified olignonucleotides, there has been no accurate prediction method available. Here we describe the potential of estimating melting temperature (T(m)) for nonstandard oligonucleotides by using the correlation of the experimental T(m) with the calculated duplex binding energy (BE) for oligonucleotides of a given length. This method has been automated into a standardized molecular dynamics (MD) protocol through Pipeline Pilot (PP) using the CHARMm component in Discovery Studio (DS). Results will be presented showing the correlation of the predicted data with experiment for both standard and chemically modified siRNA and AON.
Assuntos
Química Farmacêutica/métodos , DNA/análise , Terapia Genética/métodos , Simulação de Dinâmica Molecular , Oligonucleotídeos Antissenso/análise , Oligonucleotídeos/análise , Preparações Farmacêuticas/análise , RNA Interferente Pequeno/análise , Automação Laboratorial , DNA/química , DNA/metabolismo , Estabilidade de Medicamentos , Humanos , Terapia de Alvo Molecular/métodos , Conformação de Ácido Nucleico , Ácidos Nucleicos Heteroduplexes/química , Ácidos Nucleicos Heteroduplexes/genética , Oligonucleotídeos/química , Oligonucleotídeos/metabolismo , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/metabolismo , Preparações Farmacêuticas/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/metabolismo , Espectrofotometria , Termodinâmica , Temperatura de TransiçãoRESUMO
Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC50 =100â nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Inibidores do Citocromo P-450 CYP2C8/síntese química , Inibidores do Citocromo P-450 CYP2C8/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.
Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Humanos , Linhagem Celular Tumoral , Ensaios de Triagem em Larga Escala , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/efeitos dos fármacosRESUMO
By targeting an extended region of the conventional 'DFG-out' pocket of p38alpha, while minimizing interactions with the specificity pocket and eliminating interactions with the adenine binding site, we are able to design and synthesize a number of pyrazole-urea based DFG-out p38alpha inhibitors with good potencies, and excellent selectivity.
Assuntos
Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Adenina/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Microssomos/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Joint replacement surgery is a highly effective treatment option for patients with severe osteoarthritis (OA) of the hip and knee when other treatments have failed. Unfortunately, as a result of the COVID-19 pandemic, a temporary suspension of non-urgent elective surgery was implemented. Thousands of patients currently awaiting hip and knee replacements have been affected. Many of these patients will present to their general practitioners for symptom management during this interim period. OBJECTIVE: The purpose of this article is to summarise current recommendations for the non-operative management of patients with symptomatic OA. DISCUSSION: Non-operative treatment modalities for OA include education, lifestyle modification and exercise, mass reduction, physiotherapy, orthoses, psychology, pharmaceuticals and injections. Multimodal therapy is required for patients with severe symptoms. A number of useful online resources are presented, as access to public allied health services may be limited because of the COVID-19 pandemic.