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1.
J Immunother Cancer ; 9(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33408094

RESUMO

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. METHODS: Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. RESULTS: CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. CONCLUSION: CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.

2.
Biopharm Drug Dispos ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33354831

RESUMO

Transforming growth factor beta (TGF-ß) is a pleiotropic cytokine that has a wide array of biological effects. For decades, tumor biology implicated TGF-ß as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-ß pathway. BMS-986260 is a small molecule, selective TGF-ßR1 kinase inhibitor that was under preclinical development for oncology. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clinical efficacious dose. The human clearance is predicted to be low, 4.25 ml/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclinical species. Taken together, the projected clinical efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclinical PK characterization and pharmacodynamics-based efficacious dose projection of a novel small molecule TGF-ßR1 inhibitor.

3.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

4.
ACS Med Chem Lett ; 11(2): 172-178, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071685

RESUMO

Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

5.
PLoS One ; 14(3): e0212670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913212

RESUMO

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.


Assuntos
Imunidade Celular , Vigilância Imunológica , Linfócitos/imunologia , Neoplasias Experimentais/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Linfócitos/patologia , Camundongos , Camundongos Mutantes , Neoplasias Experimentais/genética , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Microambiente Tumoral/genética
7.
BMC Musculoskelet Disord ; 15: 409, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25477192

RESUMO

BACKGROUND: The impact of anti-TNF, corticosteroid and analgesic therapy on inflammation and pain was evaluated in a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model using Etanercept, Dexamethasone and Buprenorphine. METHODS: Multiple flares of arthritis were induced with an intra-articular injection of SCW in the hind ankle on day 1, followed by intravenous challenges on days 21 and 42. Inflammation and pain were monitored in the hind paws. Cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed. RESULTS: Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle which resolved within 4 days (Flare 1). Intravenous injection 20 days after sensitization resulted in an increase in ankle diameter and pain, which partially resolved in 8 days (Flare 2). The subsequent intra-venous injection in the same animals 14 days after resulted in a more chronic disease with inflammation and pain persisting over a period of 10 days (Flare 3). In Flare 2, therapeutic administration of Dexamethasone inhibited paw swelling (95%; P<0.001) and pain (55%; P<0.05). Therapeutic administration of Buprenorphine inhibited pain (80%; P<0.001) without affecting paw swelling (0%). Prophylactic administration of Etanercept in Flare 2 inhibited paw swelling (≥60%; P<0.001) and pain by ≥30%. Expression of IL-1ß, IL-6, MCP-1 and CINC was reduced by >50% (P<0.001). Treatment with Etanercept in Flare 3 inhibited paw swelling by 60% (P<0.001) and pain by 25%. Prior treatment with Etanercept in Flare 2 followed by re-administration in Flare 3 led to a complete loss in the efficacy of Etanercept. Systemic exposure of Etanercept corroborated with lack of efficacy. Dexamethasone inhibited inflammation and pain in both Flares 2 and 3 (P<0.001). CONCLUSIONS: We established a novel multi-flare SCW arthritis model enabling drug intervention in different stages of disease. We show for the first time the evaluation of inflammation and pain simultaneously in this model. Etanercept and Dexamethasone inhibited inflammation, pain and proinflammatory cytokines in this model. Taken together, this model facilitates the assessment of anti-rheumatic agents targeting inflammation and pain in the multiple flare paradigm and offers a powerful tool for drug discovery.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Parede Celular , Imunoglobulina G/uso terapêutico , Dor/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Streptococcus , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Etanercepte , Feminino , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Dor/induzido quimicamente , Dor/patologia , Ratos , Ratos Endogâmicos Lew
8.
J Neuroimmunol ; 239(1-2): 37-43, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-21911260

RESUMO

Immunological responses to protect against excessive inflammation can be regulated by the central nervous system through the cholinergic anti-inflammatory pathway wherein acetylcholine released from vagus nerves can inhibit inflammatory cytokines. Although a role for the α7 nicotinic acetylcholine receptor (α7 nAChR) in mediating this pathway has been suggested, pharmacological modulation of the pathway by selective agonists remains to be further elucidated. In this study, the role of α7 nAChRs in the regulation of TNF-α release was investigated using high affinity and selective α7 nAChR agonists in mouse peritoneal macrophage and human whole blood in vitro, and in mouse serum in vivo. In mouse peritoneal macrophages, LPS-induced TNF-α release in vitro was inhibited by a selective α7 nAChR agonist, A-833834 (5-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridazin-3-yl]-1H-indole), and that effect was attenuated by α7 nAChR antagonist methyllycaconitine. The inhibitory effect of A-833834 on LPS-induced TNF-α release was also observed in human whole blood in vitro. I.v. LPS-induced TNF-α release in mouse serum was attenuated following i.p. administration of A-833834. Similarly, i.v. LPS-induced TNF-α release in mouse serum was also attenuated following i.p. administration of A-585539, another α7 nAChR agonist with limited brain penetration, suggesting that these effects are mediated by peripheral α7 nAChRs. A-833834 was also efficacious in suppressing TNF-α release in mouse serum following oral administration in zymosan-induced peritonitis. These studies collectively demonstrate that selectively targeting α7 nAChRs could offer a novel therapeutic modality to treat acute and chronic inflammatory disease states.


Assuntos
Agonistas Nicotínicos/sangue , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/fisiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citocinas/antagonistas & inibidores , Citocinas/sangue , Citocinas/metabolismo , Feminino , Humanos , Mediadores da Inflamação/agonistas , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/sangue , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Oócitos , Peritonite/tratamento farmacológico , Peritonite/imunologia , Peritonite/patologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/imunologia , Receptores Nicotínicos/sangue , Receptores Nicotínicos/metabolismo , Fator de Necrose Tumoral alfa/sangue , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7
9.
J Immunol ; 182(12): 7482-9, 2009 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-19494271

RESUMO

The Bcl-2 family of proteins plays a critical role in controlling immune responses by regulating the expansion and contraction of activated lymphocyte clones by apoptosis. ABT-737, which was originally developed for oncology, is a potent inhibitor of Bcl-2, Bcl-x(L), and Bcl-w protein function. There is evidence that Bcl-2-associated dysregulation of lymphocyte apoptosis may contribute to the pathogenesis of autoimmunity and lead to the development of autoimmune diseases. In this study, we report that ABT-737 treatment resulted in potent inhibition of lymphocyte proliferation as measured by in vitro mitogenic or ex vivo Ag-specific stimulation. More importantly, ABT-737 significantly reduced disease severity in tissue-specific and systemic animal models of autoimmunity. Bcl-2 family antagonism by ABT-737 was efficacious in treating animal models of arthritis and lupus. Our results suggest that treatment with a Bcl-2 family antagonist represents a novel and potentially attractive therapeutic approach for the clinical treatment of autoimmunity.


Assuntos
Autoimunidade/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Nitrofenóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Hemocianinas/imunologia , Humanos , Hipersensibilidade Tardia/imunologia , Interferon-alfa/farmacologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Especificidade por Substrato
10.
Nat Biotechnol ; 25(11): 1290-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17934452

RESUMO

For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases.


Assuntos
Anticorpos Biespecíficos/biossíntese , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/biossíntese , Artrite Experimental/tratamento farmacológico , Região Variável de Imunoglobulina/biossíntese , Engenharia de Proteínas , Animais , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/patologia , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Humanos , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/metabolismo , Região Variável de Imunoglobulina/uso terapêutico , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/imunologia , Camundongos , Estrutura Terciária de Proteína , Ratos
11.
J Pak Med Assoc ; 57(3): 159-62, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17432028

RESUMO

OBJECTIVE: To assess the frequency of depression among hospitalized patients, the socio-demographic variables associated with depression and the number of cases referred by physicians to Psychiatry. METHODS: A cross-sectional study was carried out at the Aga Khan University Hospital Karachi. An anonymous Urdu version of the WHO-developed self-reporting questionnaire (SRQ) was administered to inpatients meeting the inclusion criteria. Data was analyzed by SPSS version 13.0. RESULT: Of the 225 patients approached, 178 completed the questionnaire (men= 45.2%, women = 54.8%). The mean age of the sample was 45.2 years. Out of the total 30.5% of patients were identified as having probable depression, among which housewives were more likely to be depressed compared to others (p=0.031). Among variable comparison, there with secondary school education or below and those with psychiatric co-morbidities, showed significantly greater prevalence of depression (p=0.003) and (p=0.005) respectively. Attending physicians correctly diagnosed 7 (13%) patients and referred only 3 patients to Psychiatry over the previous month. CONCLUSION: The prevalence of depression among inpatients is comparable to that in the general population. Being a housewife, level at or below secondary school education and having a past psychiatric history are significant factors associated with depression in medical inpatients. A very small number of depressed cases were referred to a psychiatrist.


Assuntos
Depressão/epidemiologia , Pacientes Internados , Psiquiatria/métodos , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Prevalência , Fatores de Risco
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