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1.
Proc Natl Acad Sci U S A ; 114(2): 370-375, 2017 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-28011764

RESUMEN

Glioblastoma multiforme (GBM) is an intractable tumor despite therapeutic advances, principally because of its invasive properties. Radiation is a staple in therapeutic regimens, although cells surviving radiation can become more aggressive and invasive. Subtraction hybridization identified melanoma differentiation-associated gene 9 [MDA-9/Syntenin; syndecan-binding protein (SDCBP)] as a differentially regulated gene associated with aggressive cancer phenotypes in melanoma. MDA-9/Syntenin, a highly conserved double-PDZ domain-containing scaffolding protein, is robustly expressed in human-derived GBM cell lines and patient samples, with expression increasing with tumor grade and correlating with shorter survival times and poorer response to radiotherapy. Knockdown of MDA-9/Syntenin sensitizes GBM cells to radiation, reducing postradiation invasion gains. Radiation induces Src and EGFRvIII signaling, which is abrogated through MDA-9/Syntenin down-regulation. A specific inhibitor of MDA-9/Syntenin activity, PDZ1i (113B7), identified through NMR-guided fragment-based drug design, inhibited MDA-9/Syntenin binding to EGFRvIII, which increased following radiation. Both genetic (shmda-9) and pharmacological (PDZ1i) targeting of MDA-9/Syntenin reduced invasion gains in GBM cells following radiation. Although not affecting normal astrocyte survival when combined with radiation, PDZ1i radiosensitized GBM cells. PDZ1i inhibited crucial GBM signaling involving FAK and mutant EGFR, EGFRvIII, and abrogated gains in secreted proteases, MMP-2 and MMP-9, following radiation. In an in vivo glioma model, PDZ1i resulted in smaller, less invasive tumors and enhanced survival. When combined with radiation, survival gains exceeded radiotherapy alone. MDA-9/Syntenin (SDCBP) provides a direct target for therapy of aggressive cancers such as GBM, and defined small-molecule inhibitors such as PDZ1i hold promise to advance targeted brain cancer therapy.


Asunto(s)
Glioblastoma/genética , Invasividad Neoplásica/genética , Sinteninas/genética , Animales , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , Humanos , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Melanoma/genética , Ratones , Ratones Desnudos , Dominios PDZ/genética , Transducción de Señal/genética , Familia-src Quinasas/genética
2.
Curr Med Chem ; 31(10): 1289-1295, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37143268

RESUMEN

This patent describes the synthesis of compounds, methods, and compositions for preventing, treating, and/or curing Covid-19, human coronavirus, and enterovirus infections. Some peptidomimetic compounds are very potent and could be a game changer in new treatment therapy for COVID-19.


Asunto(s)
COVID-19 , Infecciones por Enterovirus , Enterovirus , Peptidomiméticos , Humanos , Peptidomiméticos/uso terapéutico
3.
Recent Pat Anticancer Drug Discov ; 19(2): 253-255, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-36852816

RESUMEN

The patent describes novel useful compounds, such as PI3K protein kinase inhibitors, in particular as PI3K delta (δ) and/or gamma (γ) protein kinase modulators. The present disclosure also provides methods for preparing PI3K protein kinase inhibitors, pharmaceutical compositions containing them, and methods of treatment, prevention, and amelioration of PI3K kinase-mediated diseases, and disorders.


Asunto(s)
Neoplasias , Fosfatidilinositol 3-Quinasas , Humanos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Patentes como Asunto , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa
4.
Front Pharmacol ; 15: 1337436, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38410131

RESUMEN

IC50 = 11 nM (PI3Kδ); 244 nM (PI3Kα); 424 nM (PI3Kß), 2,230 nM (PI3Kγ).

5.
Curr Med Chem ; 2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37493157

RESUMEN

This paper describes the synthesis of some heteroaryl compounds and compositions comprising an effective amount of one or more such compounds and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway, comprising administering an adequate amount of a heteroaryl compound to a patient in need thereof. These compounds are mTOR/PI3K/Akt pathway inhibitors.

6.
Curr Med Chem ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37605404

RESUMEN

This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).

7.
Curr Med Chem ; 2023 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-37818564

RESUMEN

Mantle Cell Lymphoma (MCL) is an aggressive subtype of Non-hodgkin's Lymphoma (NHL). Bruton Tyrosine Kinase (BTK) is a non receptor tyrosine kinase, and is one of the therapeutic targets for B-cell-driven malignancies. Approved covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib are associated with treatment limitations due to off-target side effects and the development of C481 substitution resistance mutations. Pirtobrutinib was approved by the US FDA on January 27, 2023, for the treatment of relapsed or refractory mantle cell lymphoma, including the resistance to covalent BTK inhibitors. In this perspective, physicochemical properties, synthesis, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interactions, and treatment-emergent adverse events of pirtobrutinib are discussed.

8.
Curr Med Chem ; 30(12): 1458-1461, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36154584

RESUMEN

COVID-19 is a contagious disease. Paxlovid, a combination of Nirmatrelvir and Ritonavir, was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19 on December 22, 2021. These are peptidomimetic coronavirus main protease inhibitors. Nirmatrelvir is a proline derivative. The present patent describes similar proline- like compounds, their preparation, use, pharmaceutical composition, and treatment.


Asunto(s)
COVID-19 , Estados Unidos , Humanos , Lactamas , Prolina/uso terapéutico , Antivirales/uso terapéutico
9.
Anticancer Agents Med Chem ; 23(8): 979-980, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36443974

RESUMEN

This application describes the synthesis of new 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione derivatives and methods of using these compounds as KRAS covalent inhibitors. This class of compounds is useful for treating cancer and other diseases associated with KRAS activity.


Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación
10.
Recent Pat Anticancer Drug Discov ; 18(4): 549-551, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36476427

RESUMEN

The present disclosure relates to p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating various diseases such as cancer, rheumatoid arthritis, amyotrophic lateral sclerosis, cystic fibrosis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, COVID-19, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).


Asunto(s)
COVID-19 , Proteína Quinasa 14 Activada por Mitógenos , Neoplasias , Humanos , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Benzamidas , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Preparaciones Farmacéuticas
11.
Curr Med Chem ; 30(38): 4278-4282, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36797599

RESUMEN

Atopic dermatitis is epidermal hyperplasia, skin barrier dysfunction, and the aberrant activation of immune cells. Janus kinase (JAK) is a family of cytoplasmic nonreceptor tyrosine kinases that consists of four members, such as JAK1, JAK2, JAK3, and TYK2. The JAK signaling pathway plays a critical role in a wide range of autoimmune and inflammatory diseases, including atopic dermatitis. Abrocitinib is an orally bioavailable and selective JAK1 inhibitor, and it was approved in January, 2022, for the treatment of atopic dermatitis. The chemical structure and physical properties of abrocitinib, its synthesis, mechanism of action, and pharmacokinetic profile are summarized.


Asunto(s)
Dermatitis Atópica , Inhibidores de las Cinasas Janus , Humanos , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus
12.
Anticancer Agents Med Chem ; 23(12): 1355-1360, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36959157

RESUMEN

Myelofibrosis is one kind of bone marrow blood cancer that gives mainly bone marrow scarring. JAK families include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) and they control hematopoiesis and immune cell function. JAK-STAT pathways have the critical roles in the pathogenesis of a variety of autoimmune and inflammatory diseases such as myelofibrosis. The 8 JAK inhibitors are approved by the US FDA for the treatment of various diseases. Abrocitinib, baricitinib, oclacitinib, ruxolitinib, tofacitinib, upadacitinib, fedratinib, and pactrinib with their IC50 values against JAK1, JAK2, JAK3, and TYK2 are included. All approved JAK inhibitors with structural similarities and dissimilarities are summarized. The development story of pacritinib and new design route to overcome intellectual property-related issues by connecting the A ring and C ring to form the macrocyclic compounds like 16 without compromising the binding modes in the hinge region are discussed. By using the powerful ring-closing metathesis (RCM), they designed and synthesized and delivered FDA approved pacritinib. In this short perspective, the chemical structure, physicochemical properties, mechanism of action, drug-interactions, adverse events, and pharmacokinetic profile of pacritinib are summarized. Detailed step by step synthesis of pacritinib is provided. Pacritinib is an orally bioavailable and isoform selective JAK-2 inhibitor for the treatment of patients with myelofibrosis. Detailed metabolism pathway with proper explanation is discussed.


Asunto(s)
Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/inducido químicamente , Janus Quinasa 2 , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
13.
Curr Med Chem ; 2023 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-37143269

RESUMEN

Elacestrant was approved by the US FDA on January 27, 2023, for treating postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression prior to using at least one line of endocrine therapy. In this short perspective, physicochemical properties, dosage and administration, mechanism of action, pharmacodynamics, pharmacokinetics, drug interaction, and treatment-related adverse reactions of elacestrant are summarized.

14.
Curr Med Chem ; 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37231730

RESUMEN

The application describes the synthesis of 1H-pyrazolo[4,3-H]quinazoline compounds for treating cell proliferation dysfunction and is a broad-spectrum and strongly-active inhibitor for a cell cyclin-dependent kinase (CDK).

15.
Anticancer Agents Med Chem ; 23(14): 1697-1700, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37157195

RESUMEN

The present application reports a series of novel Arcyriaflavin-A derivatives as PIM kinase inhibitors for the effective treatment of cancer. The application also describes the synthesis of compounds in detail, use, pharmaceutical composition, pharmaceutically acceptable salts, and treatment.


Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas c-pim-1 , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Línea Celular Tumoral
16.
Artículo en Inglés | MEDLINE | ID: mdl-36803749

RESUMEN

Diaminopyrimidine compounds having the following general structure (I), compositions comprising an effective amount of a diaminopyrimidine compound, and methods for treating or preventing fibrotic liver disorders or other diseases associated with the JNK pathway are discussed in this patent study.


Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos , Hepatopatías , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas
17.
Curr Med Chem ; 30(37): 4170-4175, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36803759

RESUMEN

Oteseconazole was approved by the US FDA in April 2022. It is the first approved selective and orally bioavailable CYP51 inhibitor for the treatment of patients with recurrent Vulvovaginal candidiasis. Herein, we describe its dosage, administration, chemical structure, physical properties, synthesis, mechanism of action, and pharmacokinetics.


Asunto(s)
Candidiasis Vulvovaginal , Femenino , Humanos , Candidiasis Vulvovaginal/tratamiento farmacológico , Esterol 14-Desmetilasa/química , Antifúngicos/farmacología , Antifúngicos/uso terapéutico
18.
Curr Med Chem ; 2023 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-37259937

RESUMEN

This patent describes the series of compounds and their pharmaceutically acceptable salts, such as compound K7 (as a representative potent compound). These protein kinase C selective inhibitors are useful for treating diabetes mellitus and its complications, cancer, ischemia, inflammation, central nervous system disorders, cardiovascular disease, Alzheimer's disease, dermatological disease pression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ.

19.
Bioorg Med Chem ; 19(8): 2582-8, 2011 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-21458276

RESUMEN

We report comprehensive structure-activity relationship studies on a novel series of c-Jun N-terminal kinase (JNK) inhibitors. Intriguingly, the compounds have a dual inhibitory activity by functioning as both ATP and JIP mimetics, possibly by binding to both the ATP binding site and to the docking site of the kinase. Several of such novel compounds display potent JNK inhibitory profiles both in vitro and in cell.


Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Tiofenos/farmacología , Adenosina Trifosfato , Sitios de Unión , Línea Celular , Diseño de Fármacos , Humanos , Imitación Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Tiofenos/química
20.
Proc Natl Acad Sci U S A ; 105(43): 16809-13, 2008 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-18922779

RESUMEN

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Dioxanos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/farmacología , Animales , Unión Competitiva , Enfermedad Hepática Inducida por Sustancias y Drogas , Diabetes Mellitus Experimental/tratamiento farmacológico , Resistencia a la Insulina , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Hepatopatías/prevención & control , Ratones , Imitación Molecular , Fosforilación/efectos de los fármacos , Unión Proteica , Transducción de Señal
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