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1.
J Med Chem ; 67(8): 6456-6494, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38574366

RESUMEN

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.


Asunto(s)
ADN , Descubrimiento de Drogas , Interleucina-17 , Bibliotecas de Moléculas Pequeñas , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , ADN/metabolismo , ADN/química , Humanos , Animales , Relación Estructura-Actividad , Unión Proteica , Ratones
2.
J Med Chem ; 66(7): 5041-5060, 2023 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-36948210

RESUMEN

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.


Asunto(s)
Neoplasias , Ubiquitina-Proteína Ligasas , Humanos , Ligandos , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Portadoras/química
3.
Bioorg Med Chem Lett ; 75: 128948, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35987508

RESUMEN

The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.


Asunto(s)
Antineoplásicos , Proteínas Proto-Oncogénicas c-met , Antineoplásicos/farmacología , Línea Celular Tumoral , ADN , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/química
4.
J Med Chem ; 64(8): 5049-5066, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33844532

RESUMEN

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.


Asunto(s)
ADN/química , Receptor alfa de Estrógeno/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Clic , ADN/metabolismo , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Antagonistas de Estrógenos/uso terapéutico , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/genética , Femenino , Semivida , Humanos , Indoles/química , Indoles/metabolismo , Cinética , Ratones , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Med Chem ; 64(6): 3165-3184, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33683117

RESUMEN

Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa c-Mer/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Minería de Datos , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Tirosina Quinasa c-Mer/química , Tirosina Quinasa c-Mer/metabolismo
6.
Nat Commun ; 6: 7645, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26134520

RESUMEN

SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.


Asunto(s)
Lisina/metabolismo , Sirtuina 1/química , Secuencia de Aminoácidos , Sitios de Unión/genética , Dominio Catalítico/genética , Cristalización , Cristalografía por Rayos X , Medición de Intercambio de Deuterio , Escherichia coli , Vectores Genéticos , Humanos , Espectrometría de Masas , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Unión Proteica , Sirtuina 1/genética , Sirtuina 1/metabolismo , Transfección
7.
Cell Cycle ; 12(14): 2233-40, 2013 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-23892437

RESUMEN

SIRT1 is an NAD (+) -dependent deacetylase that counteracts multiple disease states associated with aging and may underlie some of the health benefits of calorie restriction. Understanding how SIRT1 is regulated in vivo could therefore lead to new strategies to treat age-related diseases. SIRT1 forms a stable complex with DBC1, an endogenous inhibitor. Little is known regarding the biochemical nature of SIRT1-DBC1 complex formation, how it is regulated and whether or not it is possible to block this interaction pharmacologically. In this study, we show that critical residues within the catalytic core of SIRT1 mediate binding to DBC1 via its N-terminal region, and that several carboxamide SIRT1 inhibitors, including EX-527, can completely block this interaction. We identify two acetylation sites on DBC1 that regulate its ability to bind SIRT1 and suppress its activity. Furthermore, we show that DBC1 itself is a substrate for SIRT1. Surprisingly, the effect of EX-527 on SIRT1-DBC1 binding is independent of DBC1 acetylation. Together, these data show that protein acetylation serves as an endogenous regulatory mechanism for SIRT1-DBC1 binding and illuminate a new path to developing small-molecule modulators of SIRT1.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carbazoles/farmacología , Regulación de la Expresión Génica , Inhibidores de Histona Desacetilasas/farmacología , Procesamiento Proteico-Postraduccional , Sirtuina 1/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Sitios de Unión , Línea Celular Tumoral , Genes Reporteros , Humanos , Luciferasas/genética , Unión Proteica/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Especificidad por Sustrato
8.
J Med Chem ; 56(9): 3666-79, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23570514

RESUMEN

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.


Asunto(s)
Descubrimiento de Drogas , Pirimidinas/química , Pirimidinas/farmacología , Sirtuinas/antagonistas & inhibidores , Humanos , Modelos Moleculares , Conformación Proteica , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/química , Sirtuina 2/antagonistas & inhibidores , Sirtuina 2/química , Sirtuina 3/antagonistas & inhibidores , Sirtuina 3/química , Sirtuinas/química
9.
Science ; 339(6124): 1216-9, 2013 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-23471411

RESUMEN

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.


Asunto(s)
Sirtuina 1/química , Sirtuina 1/metabolismo , Estilbenos/farmacología , Regulación Alostérica , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Células Cultivadas , Activación Enzimática , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/genética , Ácido Glutámico/química , Ácido Glutámico/genética , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Datos de Secuencia Molecular , Mioblastos/efectos de los fármacos , Mioblastos/enzimología , Estructura Terciaria de Proteína , Resveratrol , Sirtuina 1/genética , Estilbenos/química , Especificidad por Sustrato
10.
Bioorg Med Chem Lett ; 19(8): 2350-3, 2009 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-19303289

RESUMEN

SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.


Asunto(s)
Oxazoles/síntesis química , Oxazoles/metabolismo , Piridinas/síntesis química , Piridinas/metabolismo , Sirtuinas/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Humanos , Ratones , Ratones Transgénicos , Oxazoles/farmacología , Piridinas/farmacología , Ratas , Ratas Zucker , Sirtuina 1 , Sirtuinas/agonistas , Relación Estructura-Actividad
11.
J Med Chem ; 52(5): 1275-83, 2009 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-19199480

RESUMEN

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.


Asunto(s)
Activadores de Enzimas/síntesis química , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Quinoxalinas/síntesis química , Sirtuina 1/metabolismo , Tiazoles/síntesis química , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Imidazoles/química , Imidazoles/farmacología , Ratones , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Ratas Zucker , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
12.
Nature ; 450(7170): 712-6, 2007 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-18046409

RESUMEN

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.


Asunto(s)
Restricción Calórica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sirtuinas/agonistas , Acetilación , Sitio Alostérico , Animales , Glucemia/metabolismo , Dominio Catalítico , Línea Celular , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Drosophila melanogaster , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Insulina/metabolismo , Insulina/farmacología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Resveratrol , Sirtuina 1 , Sirtuinas/metabolismo , Estilbenos/química , Estilbenos/farmacología
13.
Inorg Chem ; 42(21): 6749-63, 2003 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-14552627

RESUMEN

A series of 14-, 15-, and 16-membered nickel(II) cyclidene macrocycles appended with 2-aminoethyl(2-pyridine) receptors I-III, respectively, were prepared and characterized by X-ray crystallography and NMR techniques. The 14- and 15-membered macrocycles I and II exist in a planar or extended Z-configuration, whereas the 16-membered macrocycle III was saddle shaped and had two asymmetric configurations in the unit cell (IIIa in a "capped" configuration and IIIb in an "open" configuration). Variable-temperature (1)H NMR studies of III in CD(3)CN were conducted (25-65 degrees C), and at room temperature, the interconversion between capping and uncapping is slow on the NMR time scale, resulting in a broad spectrum, whereas at 65 degrees C, interconversion was fast. (1)H NMR binding studies indicated I-III bind unsaturated dicarboxylic acids in a 1:1 stoichiometry with binding constants approaching 400 M(-)(1) in CD(3)CN, and the binding strength was dependent on the shape of the macrocyclic cyclidene platforms, whereas monocarboxylic acids were not bound. Generally, the planar 14-membered cyclidene I bound diacids the weakest and the 16-membered cyclidene III bound diacids the strongest. The presence of nuclear Overhauser effect spectrometry cross peaks in a 20 mM solution of 1:1 II-maleic acid indicates that the binding mode is ditopic with the guest being encapsulated by the aminoethylpyridine arms above the macrocyclic framework.


Asunto(s)
Ácidos Dicarboxílicos/química , Níquel/química , Piridinas/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular
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