RESUMO
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.
Assuntos
Proteínas Nucleares/antagonistas & inibidores , Piridonas/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Camundongos , Microssomos/metabolismo , Simulação de Dinâmica Molecular , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Piridonas/farmacocinética , Piridonas/farmacologia , Piridonas/uso terapêutico , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transplante HeterólogoRESUMO
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.
Assuntos
Antineoplásicos/química , Proteínas Nucleares/antagonistas & inibidores , Pirróis/química , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Camundongos , Simulação de Dinâmica Molecular , Mieloma Múltiplo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Pirróis/síntese química , Pirróis/farmacocinética , Pirróis/uso terapêutico , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Transplante HeterólogoRESUMO
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.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Citocinas/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/química , Citocinas/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Camundongos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/química , Nicotinamida Fosforribosiltransferase/metabolismo , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
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.
Assuntos
Desempenho Atlético , Jogos e Brinquedos , Futebol , Esportes Juvenis , Adolescente , Criança , Comportamento Infantil , Futebol Americano , Alemanha , Humanos , Estudos Longitudinais , Masculino , Análise Multivariada , EsportesRESUMO
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.
RESUMO
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.
Assuntos
Desenho de Fármacos , Compostos Heterocíclicos/química , Indazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Indazóis/química , Indazóis/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Desenho de Fármacos , Indazóis , Inibidores de Proteínas Quinases , Ciclização , Indazóis/síntese química , Indazóis/farmacologia , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Receptor IGF Tipo 1/antagonistas & inibidores , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Ratos , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-AtividadeRESUMO
The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
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).
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Descoberta de Drogas/métodos , Piridinas/química , Piridinas/metabolismo , Pirróis/química , Pirróis/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Animais , Feminino , Células HeLa , Humanos , Camundongos , Camundongos SCID , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Piridinas/farmacologia , Pirróis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dimerização , Desenho de Fármacos , Humanos , Pulmão/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Fosforilação , Pirimidinas/química , Receptores Proteína Tirosina Quinases/química , Transdução de SinaisRESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Quinases/metabolismo , Antineoplásicos/síntese química , Benzodiazepinonas/síntese química , Linhagem Celular Tumoral/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Inibidores Enzimáticos/síntese química , Células HeLa , Humanos , Modelos Químicos , Ligação Proteica , Relação Estrutura-AtividadeAssuntos
Deformidades Adquiridas do Pé/prevenção & controle , Dermatoses do Pé/terapia , Ceratose/terapia , Doenças da Unha/terapia , Comportamento Cooperativo , Tabela de Remuneração de Serviços , Deformidades Adquiridas do Pé/economia , Deformidades Adquiridas do Pé/etiologia , Dermatoses do Pé/diagnóstico , Dermatoses do Pé/economia , Dermatoses do Pé/etiologia , Alemanha , Humanos , Comunicação Interdisciplinar , Ceratose/diagnóstico , Ceratose/economia , Ceratose/etiologia , Doenças da Unha/diagnóstico , Doenças da Unha/economia , Doenças da Unha/etiologia , Unhas Malformadas/diagnóstico , Unhas Malformadas/economia , Unhas Malformadas/etiologia , Unhas Malformadas/terapia , Programas Nacionais de Saúde/economia , Podiatria , Mecanismo de Reembolso/economia , SapatosRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Compostos Macrocíclicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Ureia/análogos & derivados , Ureia/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Dano ao DNA , Doxorrubicina/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologiaRESUMO
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.