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1.
Bioorg Med Chem Lett ; 52: 128406, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624491

RESUMO

Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead.


Assuntos
Acrilamidas/farmacologia , Afatinib/farmacologia , Compostos de Anilina/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Acrilamidas/química , Afatinib/química , Compostos de Anilina/química , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 30(14): 127261, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32527559

RESUMO

Bruton tyrosine kinase (BTK) is an important target in oncology and (auto)immunity. Various BTK inhibitors have been approved or are currently in clinical development. A novel BTK inhibitor series was developed starting with a quinazoline core. Moving from a quinazoline to a quinoline core provided a handle for selectivity for BTK over EGFR and resulted in the identification of potent and selective BTK inhibitors with good potency in human whole blood assay. Furthermore, proof of concept of this series for BTK inhibition was shown in an in vivo mouse model using one of the compounds identified.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/química , Relação Estrutura-Atividade
3.
J Pharmacol Exp Ther ; 363(2): 240-252, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28882879

RESUMO

Several small-molecule Bruton tyrosine kinase (BTK) inhibitors are in development for B cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib [compound 1, ACP-196 (4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-(2-pyridyl)benzamide)]. Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential. Acalabrutinib demonstrated higher biochemical and cellular selectivity than ibrutinib and spebrutinib (compounds 2 and 3, respectively). Importantly, off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK), were not inhibited. Determination of the inhibitory potential of anti-immunoglobulin M-induced CD69 expression in human peripheral blood mononuclear cells and whole blood demonstrated that acalabrutinib is a potent functional BTK inhibitor. In vivo evaluation in mice revealed that acalabrutinib is more potent than ibrutinib and spebrutinib. Preclinical and clinical studies showed that the level and duration of BTK occupancy correlates with in vivo efficacy. Evaluation of the pharmacokinetic properties of acalabrutinib in healthy adult volunteers demonstrated rapid absorption and fast elimination. In these healthy individuals, a single oral dose of 100 mg showed approximately 99% median target coverage at 3 and 12 hours and around 90% at 24 hours in peripheral B cells. In conclusion, acalabrutinib is a BTK inhibitor with key pharmacologic differentiators versus ibrutinib and spebrutinib and is currently being evaluated in clinical trials.


Assuntos
Benzamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/farmacologia , Tirosina Quinase da Agamaglobulinemia , Animais , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/sangue , Proteínas Tirosina Quinases/metabolismo , Pirazinas/química
4.
Bioorg Med Chem Lett ; 22(1): 613-8, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22119462

RESUMO

Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNFα is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.


Assuntos
Benzamidas/farmacologia , Química Farmacêutica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Piperidonas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Simulação por Computador , Cristalografia por Raios X/métodos , Citocinas/metabolismo , Desenho de Fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico , Humanos , Modelos Químicos , Chaperonas Moleculares , Fosforilação , Pirróis/química
5.
Bioorg Med Chem Lett ; 21(12): 3823-7, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21565498

RESUMO

The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pK(a) and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC(50) 7.4 nM) and submicromolar cellular target engagement activity (EC(50) 0.5 µM).


Assuntos
Descoberta de Drogas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Piperidinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Compostos de Espiro/síntese química , Administração Oral , Animais , Ligação Competitiva , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular/química , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Ratos , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por Substrato
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