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1.
Bioorg Med Chem Lett ; 24(4): 1138-43, 2014 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-24462666

RESUMEN

The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.


Asunto(s)
Bencimidazoles/farmacología , Descubrimiento de Drogas , Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Humanos , Quinasa I-kappa B/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-Actividad
2.
Immunohorizons ; 7(5): 366-379, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37219538

RESUMEN

CD39 (ENTPD1) is a key enzyme responsible for degradation of extracellular ATP and is upregulated in the tumor microenvironment (TME). Extracellular ATP accumulates in the TME from tissue damage and immunogenic cell death, potentially initiating proinflammatory responses that are reduced by the enzymatic activity of CD39. Degradation of ATP by CD39 and other ectonucleotidases (e.g., CD73) results in extracellular adenosine accumulation, constituting an important mechanism for tumor immune escape, angiogenesis induction, and metastasis. Thus, inhibiting CD39 enzymatic activity can inhibit tumor growth by converting a suppressive TME to a proinflammatory environment. SRF617 is an investigational, anti-CD39, fully human IgG4 Ab that binds to human CD39 with nanomolar affinity and potently inhibits its ATPase activity. In vitro functional assays using primary human immune cells demonstrate that inhibiting CD39 enhances T-cell proliferation, dendritic cell maturation/activation, and release of IL-1ß and IL-18 from macrophages. In vivo, SRF617 has significant single-agent antitumor activity in human cell line-derived xenograft models that express CD39. Pharmacodynamic studies demonstrate that target engagement of CD39 by SRF617 in the TME inhibits ATPase activity, inducing proinflammatory mechanistic changes in tumor-infiltrating leukocytes. Syngeneic tumor studies using human CD39 knock-in mice show that SRF617 can modulate CD39 levels on immune cells in vivo and can penetrate the TME of an orthotopic tumor, leading to increased CD8+ T-cell infiltration. Targeting CD39 is an attractive approach for treating cancer, and, as such, the properties of SRF617 make it an excellent drug development candidate.


Asunto(s)
Inmunoglobulina G , Activación de Linfocitos , Humanos , Animales , Ratones , Anticuerpos Monoclonales , Adenosina Trifosfatasas , Adenosina Trifosfato
3.
Bioorg Med Chem Lett ; 22(14): 4907-11, 2012 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-22704236

RESUMEN

Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38α kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38α selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics.


Asunto(s)
Amidas/química , Proteínas Hedgehog/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Amidas/farmacología , Animales , Evaluación Preclínica de Medicamentos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 22(5): 2063-9, 2012 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-22305584

RESUMEN

The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.


Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasa B , Aurora Quinasas , Compuestos Aza/química , Compuestos Aza/farmacología , Quinasa 2 Dependiente de la Ciclina/metabolismo , Diseño de Fármacos , Células HEK293 , Humanos , Quinasa I-kappa B/metabolismo , Modelos Moleculares , Neoplasias/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-Actividad
5.
Mol Cancer Res ; 10(9): 1147-57, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22859707

RESUMEN

PURPOSE: The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment. EXPERIMENTAL DESIGN: Expression of Hh pathway members and activation of the Hh pathway were analyzed in both HPSCs and pancreatic cancer cells. We tested the effects of Smoothened (SMO) inhibition with AZD8542 on tumor growth in vivo using an orthotopic model of pancreatic cancer containing varying amounts of stroma. RESULTS: HPSCs expressed high levels of SMO receptor and low levels of Hh ligands, whereas cancer cells showed the converse expression pattern. HPSC proliferation was stimulated by Sonic Hedgehog with upregulation of downstream GLI1 mRNA. These effects were abrogated by AZD8542 treatment. In an orthotopic model of pancreatic cancer, AZD8542 inhibited tumor growth only when HPSCs were present, implicating a paracrine signaling mechanism dependent on stroma. Further evidence of paracrine signaling of the Hh pathway in prostate and colon cancer models is provided, demonstrating the broader applicability of our findings. CONCLUSION: Based on the use of our novel human-derived pancreatic cancer stellate cells, our results suggest that Hh-targeted therapies primarily affect the tumor-associated stroma, rather than the epithelial compartment.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Benzamidas/farmacología , Proteínas Hedgehog/antagonistas & inhibidores , Imidazoles/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Comunicación Paracrina/efectos de los fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antineoplásicos/química , Benzamidas/química , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Imidazoles/química , Neoplasias Hepáticas/tratamiento farmacológico , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/fisiología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptor Smoothened , Regulación hacia Arriba
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