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1.
Proc Natl Acad Sci U S A ; 112(34): 10768-73, 2015 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-26261308

RESUMEN

Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.


Asunto(s)
Bencimidazoles/farmacología , Inmunosupresores/farmacología , Interleucina-17/metabolismo , Isoxazoles/farmacología , Células Th17/efectos de los fármacos , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Adulto , Anciano , Artritis Psoriásica/metabolismo , Artritis Psoriásica/patología , Azepinas/farmacología , Bencimidazoles/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Calorimetría , Células Cultivadas , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunosupresores/química , Interleucina-17/biosíntesis , Interleucina-17/genética , Isoxazoles/química , Cinética , Masculino , Persona de Mediana Edad , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Estructura Terciaria de Proteína/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Espondilitis Anquilosante/metabolismo , Espondilitis Anquilosante/patología , Relación Estructura-Actividad , Células Th17/inmunología , Triazoles/farmacología
2.
J Am Chem Soc ; 136(26): 9308-19, 2014 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-24946055

RESUMEN

Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.


Asunto(s)
Proteína de Unión a CREB/química , Proteína p300 Asociada a E1A/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Sitios de Unión , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Técnicas de Química Sintética , Cristalografía por Rayos X , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Proteína p300 Asociada a E1A/metabolismo , Recuperación de Fluorescencia tras Fotoblanqueo , Genes p53 , Células HeLa/efectos de los fármacos , Humanos , Indoles/química , Isoxazoles/química , Ligandos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-Actividad
3.
Angew Chem Int Ed Engl ; 53(24): 6126-30, 2014 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-24821300

RESUMEN

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-π interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.


Asunto(s)
Proteína de Unión a CREB/genética , Cationes/química , Epigenómica/métodos , Ligandos , Modelos Moleculares , Unión Proteica
4.
Bioorg Med Chem Lett ; 21(19): 5939-43, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21885277

RESUMEN

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.


Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferones/agonistas , Receptor Toll-Like 7/agonistas , Aldehído Oxidasa/metabolismo , Animales , Antivirales/química , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Hepacivirus/fisiología , Hepatitis C/virología , Humanos , Inyecciones Intravenosas , Inductores de Interferón/síntesis química , Inductores de Interferón/química , Inductores de Interferón/farmacocinética , Inductores de Interferón/farmacología , Microsomas Hepáticos/metabolismo , Terapia Molecular Dirigida , Peso Molecular , Purinas/síntesis química , Purinas/metabolismo , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad
7.
J Med Chem ; 60(13): 5349-5363, 2017 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-28375629

RESUMEN

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).


Asunto(s)
Proteína de Unión a CREB/antagonistas & inhibidores , Diseño de Fármacos , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Morfolinas/farmacología , Proteína de Unión a CREB/metabolismo , Química Farmacéutica , Relación Dosis-Respuesta a Droga , Proteína p300 Asociada a E1A/metabolismo , Humanos , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Relación Estructura-Actividad
8.
Medchemcomm ; 7(12): 2246-2264, 2016 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-29170712

RESUMEN

In the last five years, the development of inhibitors of bromodomains has emerged as an area of intensive worldwide research. Emerging evidence has implicated a number of non-BET bromodomains in the onset and progression of diseases such as cancer, HIV infection and inflammation. The development and use of small molecule chemical probes has been fundamental to pre-clinical evaluation of bromodomains as targets. Recent efforts are described highlighting the development of potent, selective and cell active non-BET bromodomain inhibitors and their therapeutic potential. Over half of typical bromodomains now have reported ligands, but those with atypical binding site residues remain resistant to chemical probe discovery efforts.

9.
J Med Chem ; 55(22): 9393-413, 2012 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-22924434

RESUMEN

Bromodomains, protein modules that recognize and bind to acetylated lysine, are emerging as important components of cellular machinery. These acetyl-lysine (KAc) "reader" domains are part of the write-read-erase concept that has been linked with the transfer of epigenetic information. By reading KAc marks on histones, bromodomains mediate protein-protein interactions between a diverse array of partners. There has been intense activity in developing potent and selective small molecule probes that disrupt the interaction between a given bromodomain and KAc. Rapid success has been achieved with the BET family of bromodomains, and a number of potent and selective probes have been reported. These compounds have enabled linking of the BET bromodomains with diseases, including cancer and inflammation, suggesting that bromodomains are druggable targets. Herein, we review the biology of the bromodomains and discuss the SAR for the existing small molecule probes. The biology that has been enabled by these compounds is summarized.


Asunto(s)
Histonas/metabolismo , Lisina/metabolismo , Terapia Molecular Dirigida , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Acetilación , Animales , Humanos , Proteínas Nucleares/genética , Unión Proteica , Procesamiento Proteico-Postraduccional
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