RESUMEN
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models.
Asunto(s)
Proteínas Nucleares/antagonistas & inhibidores , Piridonas/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Sitios de Unión , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Ratones , Microsomas/metabolismo , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Estructura Terciaria de Proteína , Piridonas/farmacocinética , Piridonas/farmacología , Piridonas/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
An NMR fragment screen for binders to the bromodomains of BRD4 identified 2-methyl-3-ketopyrroles 1 and 2. Elaboration of these fragments guided by structure-based design provided lead molecules with significant activity in a mouse tumor model. Further modifications to the methylpyrrole core provided compounds with improved properties and enhanced activity in a mouse model of multiple myeloma.
Asunto(s)
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inhibidores , Pirroles/química , Factores de Transcripción/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Semivida , Humanos , Ratones , Simulación de Dinámica Molecular , Mieloma Múltiple/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/uso terapéutico , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Citocinas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Citocinas/química , Citocinas/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Isoindoles/química , Isoindoles/farmacocinética , Isoindoles/farmacología , Isoindoles/uso terapéutico , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Nicotinamida Fosforribosiltransferasa/química , Nicotinamida Fosforribosiltransferasa/metabolismo , Relación Estructura-Actividad , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
This study examined contributions of different types of sport activities to the development of elite youth soccer performance. Match-play performance of 44 German male players was assessed by expert coaches twice, 24 months apart (age 11.1-13.1 years), based on videotaped 5v5 matches. Player pairs were matched by identical age and initial performance at t1. Each player was assigned to a group of either "Strong" or "Weak Responders" based on a higher or lower subsequent performance improvement at t2 within each pair (mean Δperformance 29% vs. 7%). A questionnaire recorded current and earlier amounts of organised practice/training and non-organised sporting play, in soccer and other sports, respectively. Group comparison revealed that "Strong Responders" accumulated more non-organised soccer play and organised practice/training in other sports, but not more organised soccer practice/training. Subsequent multivariate analyses (multiple linear regression analyses (MLR)) highlighted that higher resultant match-play performance at t2 was accounted for R2adj = 0.65 by performance at t1, together with more non-organised soccer play and organised engagement in other sports, respectively, and greater current, but less earlier volume of organised soccer. The findings suggest that variable early sporting experience facilitates subsequent soccer performance development in German elite youth footballers.
Asunto(s)
Rendimiento Atlético , Juego e Implementos de Juego , Fútbol , Deportes Juveniles , Adolescente , Niño , Conducta Infantil , Fútbol Americano , Alemania , Humanos , Estudios Longitudinales , Masculino , Análisis Multivariante , DeportesRESUMEN
The SARS-CoV-2 main protease (Mpro) is essential for viral replication because it is responsible for the processing of most of the non-structural proteins encoded by the virus. Inhibition of Mpro prevents viral replication and therefore constitutes an attractive antiviral strategy. We set out to develop a high-throughput Mpro enzymatic activity assay using fluorescently labeled peptide substrates. A library of fluorogenic substrates of various lengths, sequences and dye/quencher positions was prepared and tested against full length SARS-CoV-2 Mpro enzyme for optimal activity. The addition of buffers containing strongly hydrated kosmotropic anion salts, such as citrate, from the Hofmeister series significantly boosted the enzyme activity and enhanced the assay detection limit, enabling the ranking of sub-nanomolar inhibitors without relying on the low-throughput Morrison equation method. By comparing cooperativity in citrate or non-citrate buffer while titrating the Mpro enzyme concentration, we found full positive cooperativity of Mpro with citrate buffer at less than one nanomolar (nM), but at a much higher enzyme concentration (â¼320 nM) with non-citrate buffer. In addition, using a tight binding Mpro inhibitor, we confirmed there was only one active catalytical site in each Mpro monomer. Since cooperativity requires at least two binding sites, we hypothesized that citrate facilitates dimerization of Mpro at sub-nanomolar concentration as one of the mechanisms enhances Mpro catalytic efficiency. This assay has been used in high-throughput screening and structure activity relationship (SAR) studies to support medicinal chemistry efforts. IC50 values determined in this assay correlates well with EC50 values generated by a SARS-CoV-2 antiviral assay after adjusted for cell penetration.
RESUMEN
We report the synthesis and biological evaluation of 5-substituted indazoles and amino indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing [2+3] cycloaddition reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for numerous kinases such as Rock2, Gsk3ß, Aurora2 and Jak2.
Asunto(s)
Diseño de Fármacos , Indazoles , Inhibidores de Proteínas Quinasas , Ciclización , Indazoles/síntesis química , Indazoles/farmacología , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
We report the synthesis and biological evaluation of 5-substituted indazoles as kinase inhibitors. The compounds were synthesized in a parallel synthesis fashion from readily available starting materials employing heterocycle forming and multicomponent reactions and were evaluated against a panel of kinase assays. Potent inhibitors were identified for Gsk3ß, Rock2, and Egfr.
Asunto(s)
Diseño de Fármacos , Compuestos Heterocíclicos/química , Indazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
BCL-XL, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
RESUMEN
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.
RESUMEN
This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.
Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenina/química , Adenina/farmacocinética , Adenina/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Ratas , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tiazoles/farmacología , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (â¼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Descubrimiento de Drogas/métodos , Piridinas/química , Piridinas/metabolismo , Pirroles/química , Pirroles/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Animales , Femenino , Células HeLa , Humanos , Ratones , Ratones SCID , Dominios Proteicos/efectos de los fármacos , Dominios Proteicos/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Piridinas/farmacología , Pirroles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.
RESUMEN
Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.
Asunto(s)
Antineoplásicos/síntesis química , Química Farmacéutica/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Dimerización , Diseño de Fármacos , Humanos , Pulmón/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Fosforilación , Pirimidinas/química , Proteínas Tirosina Quinasas Receptoras/química , Transducción de SeñalRESUMEN
Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties via short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H3, 5HT1A, ß2AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.
RESUMEN
The synthesis and structure-activity relationships (SAR) of Chk1 inhibitors based on a 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one core are described. Specifically, an exploration of the 7 and 8 positions on this previously disclosed core afforded compounds with improved enzymatic and cellular potency.
Asunto(s)
Antineoplásicos/farmacología , Benzodiazepinonas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas/metabolismo , Antineoplásicos/síntesis química , Benzodiazepinonas/síntesis química , Línea Celular Tumoral/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Inhibidores Enzimáticos/síntesis química , Células HeLa , Humanos , Modelos Químicos , Unión Proteica , Relación Estructura-ActividadAsunto(s)
Deformidades Adquiridas del Pie/prevención & control , Dermatosis del Pie/terapia , Queratosis/terapia , Enfermedades de la Uña/terapia , Conducta Cooperativa , Tabla de Aranceles , Deformidades Adquiridas del Pie/economía , Deformidades Adquiridas del Pie/etiología , Dermatosis del Pie/diagnóstico , Dermatosis del Pie/economía , Dermatosis del Pie/etiología , Alemania , Humanos , Comunicación Interdisciplinaria , Queratosis/diagnóstico , Queratosis/economía , Queratosis/etiología , Enfermedades de la Uña/diagnóstico , Enfermedades de la Uña/economía , Enfermedades de la Uña/etiología , Uñas Malformadas/diagnóstico , Uñas Malformadas/economía , Uñas Malformadas/etiología , Uñas Malformadas/terapia , Programas Nacionales de Salud/economía , Podiatría , Mecanismo de Reembolso/economía , ZapatosRESUMEN
Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Macrocíclicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/química , Urea/análogos & derivados , Urea/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/farmacología , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Daño del ADN , Doxorrubicina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Humanos , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/farmacologíaRESUMEN
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.