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1.
Expert Opin Drug Metab Toxicol ; 16(1): 11-30, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31903790

RESUMEN

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.


Asunto(s)
Desarrollo de Medicamentos , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Humanos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/metabolismo , Receptores CCR4/antagonistas & inhibidores , Receptores CCR4/metabolismo , Receptores CCR5/efectos de los fármacos , Receptores CCR5/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Receptores de Quimiocina/metabolismo
8.
Expert Opin Investig Drugs ; 29(2): 191-196, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31928475

RESUMEN

Introduction: NASH and type 2 diabetes (T2D) are clinical definitions that overlap and result from metabolic dysfunction caused by over-nutrition relative to metabolic need. This volume details drug development programs aimed at specific NASH pathology with a focus on liver outcomes; this commentary suggests a metabolic approach that should not be overlooked based on a new understanding of insulin sensitizers.Areas covered: The overlap of NASH and T2D with respect to metabolic syndrome is discussed in the context of new understandings of insulin sensitizers. Adverse clinical outcomes in subjects with advanced NAFLD (e.g. NASH) and advanced metabolic dysfunction (e.g., T2D) are primarily due to cardiovascular issues. Clinical evidence suggests that insulin resistance and hyperinsulinemia predict adverse cardiovascular outcomes. NALFD/NASH significantly contributes to insulin resistance and hyperinsulinemia. A new insulin sensitizer that targets the newly identified mitochondrial pyruvate carrier could provide an approach.Expert opinion: A metabolic approach is needed for the treatment of NASH. Clinical studies are underway to determine whether a new insulin sensitizer that targets pyruvate metabolism can impact NASH, T2D, and cardiovascular disease. A broader view of metabolic disease may provide a more assessable way to track therapeutic benefit.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Desarrollo de Medicamentos , Humanos , Resistencia a la Insulina , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/fisiopatología , Afecciones Crónicas Múltiples , Enfermedad del Hígado Graso no Alcohólico/fisiopatología
9.
Expert Opin Investig Drugs ; 29(2): 197-204, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31948295

RESUMEN

Introduction: Fibroblast growth factor (FGF) 21 is a member of the FGF19 sub-family of signaling molecules. They have been found to act at the localized paracrine/autocrine and systemic endocrine levels because of their extracellular matrix and co-receptor protein binding characteristics. While the molecule circulates systemically, it has specificity conferred by a co-factor binding protein ß-Klotho which is preferentially expressed in hepatic and adipose tissues. This protein, in conjunction with the FGF receptor (FGFR), propagates the downstream effects of the growth factor signaling cascade, which has been linked to fat and glucose metabolism. FGF21 has been recognized as a possible pathway for the treatment of nonalcoholic fatty liver disease (NAFLD). Targeting of the FGF21/FGFR/ß-Klotho pathway may halt or reverse hepatic fat infiltration, inflammation, and fibrosis.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of two FGF21 agonist therapies in development.Expert opinion: Preclinical and clinical data justify further investigation of FGF21 agonist therapies for the treatment of NAFLD. However, issues including injection site reactions and possible effects on bone homeostasis mean that safety must be evaluated carefully.


Asunto(s)
Desarrollo de Medicamentos , Factores de Crecimiento de Fibroblastos/agonistas , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal
10.
Expert Opin Investig Drugs ; 29(2): 179-190, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31948298

RESUMEN

Introduction: Globally, deaths from liver disease are increasing and for most patients there are few curative options. Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking. Recent work has shown that Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.Areas covered: This article seeks to shed light on the dualistic role of Wnt signaling in liver regeneration following injury and how Wnt signaling can regulate scar formation. It also discusses how Wnt signaling cooperates with other classical fibrogenic signaling cascades, such as TGFß signaling. Finally, the article examines recent advances in the development of Wnt signaling pathway inhibitors and asks whether repurposing these agents as anti-fibrotic therapies is a realistic option.Expert opinion: The understanding of Wnt signaling in liver regeneration and fibrosis is in its infancy and whilst new generations of Wnt pathway inhibitors have shown anti-fibrotic effects, further research is necessary to enhance our understanding of the Wnt-landscape in different patterns of liver disease. This will accelerate the development of more specific Wnt inhibitor-based anti-fibrotics.


Asunto(s)
Cirrosis Hepática/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Animales , Cicatriz/prevención & control , Progresión de la Enfermedad , Desarrollo de Medicamentos , Humanos , Cirrosis Hepática/fisiopatología , Hepatopatías/fisiopatología , Regeneración Hepática/efectos de los fármacos
13.
Cancer Treat Rev ; 84: 101947, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31926403

RESUMEN

The ability of cancer immunotherapy to generate lasting responses in a broad spectrum of tumors has generated great enthusiasm in medical oncology. A number of new immune-based compounds have now been approved based on the recent success of immune checkpoint blockade, either administered as monotherapy or in combination with other agents. Because clinical activity is limited only to subsets of patients, two major goals of cancer immunotherapy are (1) to reliably identify responders to these current treatments, and (2) to increase the number of patients who can respond to immunotherapy by developing new strategies. These goals are critically important since the hallmark of immune-based therapies is the induction of durable immunologic and clinical responses that result in overall survival benefit. Innovative combination strategies have great potential for bringing the benefit of immunotherapy to more patients. The use of cancer vaccines to actively induce immune effectors together with other drugs, which may include immune checkpoint blockade, chemotherapy, and/or molecularly targeted agents, is a particularly attractive strategy. Cancer vaccines have been tested both to prevent or intercept the development of cancer, and to decrease established tumor burdens. No vaccine has yet been approved for either breast cancer treatment or prevention. Here, we review the history of breast cancer vaccine development, and highlight near-term opportunities for moving forward.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/prevención & control , Vacunas contra el Cáncer/uso terapéutico , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Femenino , Humanos , Inmunoterapia Activa/métodos
16.
Expert Opin Ther Pat ; 30(1): 1-13, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31825687

RESUMEN

Introduction: Peroxisome proliferator-activated receptors (PPARs), PPARα, PPARδ, and PPARγ, play an important role in the regulation of various physiological processes, specifically lipid and energy metabolism and immunity. PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are used for the treatment of hypertriglyceridemia and type 2 diabetes, respectively. PPARδ activation enhances mitochondrial and energy metabolism but PPARδ-acting drugs are not yet available. Many synthetic ligands for PPARs have been developed to expand their therapeutic applications.Areas covered: The authors searched recent patent activity regarding PPAR ligands. Novel PPARα agonists, PPARδ agonists, PPARγ agonists, PPARα/γ dual agonists, and PPARγ antagonists have been claimed for the treatment of metabolic disease and inflammatory disease. Methods for the combination of PPAR ligands with other drugs and expanded application of PPAR agonists for bone and neurological disease have been also claimed.Expert opinion: Novel PPAR ligands and the combination of PPAR ligands with other drugs have been claimed for the treatment of mitochondrial disease, inflammatory/autoimmune disease, neurological disease, and cancer in addition to metabolic diseases including dyslipidemia and type 2 diabetes. Selective therapeutic actions of PPAR ligands should be exploited to avoid adverse effects. More basic studies are needed to elucidate the molecular mechanisms of selective actions.


Asunto(s)
PPAR alfa/metabolismo , PPAR delta/metabolismo , PPAR gamma/metabolismo , Animales , Desarrollo de Medicamentos , Humanos , Ligandos , PPAR alfa/agonistas , PPAR alfa/antagonistas & inhibidores , PPAR delta/agonistas , PPAR delta/antagonistas & inhibidores , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , Patentes como Asunto
17.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31771391

RESUMEN

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/efectos adversos , Benzofuranos/farmacología , Diabetes Mellitus Tipo 2/fisiopatología , Desarrollo de Medicamentos , Humanos , Hipoglucemiantes/efectos adversos , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Patentes como Asunto , Receptores Acoplados a Proteínas G/metabolismo , Sulfonas/efectos adversos , Sulfonas/farmacología
18.
Expert Opin Investig Drugs ; 29(1): 5-14, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31815551

RESUMEN

Introduction: Kinesin spindle protein (KSP) is indispensable for the proper separation of spindle poles during mitosis. Importantly, this protein is expressed only in cells undergoing cell division and hence represents an appealing target for the treatment of cancer. Many KSP inhibitors have demonstrated a strong antitumoral effect in vitro, however, they have exhibited only limited activity in clinical trials. By contrast, the KSP inhibitor filanesib has demonstrated clinical efficacy in patients with multiple myeloma (MM).Areas covered: This article provides a comprehensive overview about the progress to date in the preclinical and clinical development of filanesib for the treatment of cancer, and particularly, MM.Expert opinion: Responses observed with filanesib alone or in combination with dexamethasone were encouraging in MM. However, the subsequent appearance of highly effective novel agents such as monoclonal antibodies, has hindered the development of agents such as filanesib that exhibit a more limited activity. Nevertheless, filanesib has shown interesting results for some patients when combined with carfilzomib and pomalidomide. Most importantly, the availability of a biomarker of response such as alpha 1-acid glycoprotein (AAG), could be key to the identification of patients that could benefit most from these combinations.


Asunto(s)
Antimitóticos/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Tiadiazoles/administración & dosificación , Animales , Antimitóticos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/metabolismo , Desarrollo de Medicamentos , Humanos , Cinesina/antagonistas & inhibidores , Mieloma Múltiple/patología , Tiadiazoles/farmacología
19.
Expert Opin Ther Pat ; 30(1): 57-81, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31815566

RESUMEN

Introduction: The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, functions as an 'epigenetic reader' that binds to acetylated lysine (KAc) residues on histone tails sophisticatedly regulating chromatin structure and gene expression. Recently, emerging evidence demonstrates that BRD4 plays a significant role in the occurrence and progression of several malignant human diseases especially cancers, making it a hot target in cancer therapy.Areas covered: This review mainly summarizes the patents of BRD4 inhibitors that have been authorized from 2013 to 2019. The patents are mostly described in terms of chemical structures, molecular mechanisms of action, pharmacological activities and potential clinical applications, including combination therapies. The development of BRD4 inhibitors in the clinical phase has been highlighted. Prospects for further development of more selective BRD4 inhibitors are provided.Expert opinion: In 2013-2019, several previously known chemical scaffolds have been further developed and disclosed. Although many small molecule BRD4 inhibitors with high potency and diverse scaffolds have been developed, the selectivity of most BRD4 inhibitors still needs to be improved. Therefore, the development of more selective small molecule inhibitors or combined use of drugs such as immunotherapy may provide new ideas for drug development.


Asunto(s)
Antineoplásicos/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Factores de Transcripción/antagonistas & inhibidores , Animales , Proteínas de Ciclo Celular/metabolismo , Desarrollo de Medicamentos , Humanos , Neoplasias/patología , Patentes como Asunto , Factores de Transcripción/metabolismo
20.
Expert Opin Drug Saf ; 19(1): 19-22, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31739696

RESUMEN

Introduction: The 18th Annual Meeting of the Safety Pharmacology Society included a session dedicated to the assessment of drug safety on the gastrointestinal (GI) system.Areas covered: GI anatomy, physiology, adverse effects (AEs) of chemical and biological therapies, and approaches to mitigate them.Expert opinion: GI AEs, albeit common and generally of minor intensity, may prolong clinical development time and reduce patient compliance.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Enfermedades Gastrointestinales/inducido químicamente , Tracto Gastrointestinal/efectos de los fármacos , Animales , Desarrollo de Medicamentos/métodos , Humanos
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