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1.
ACS Chem Biol ; 14(6): 1205-1216, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31059222

RESUMO

Access to cryptic binding pockets or allosteric sites on a kinase that present themselves when the enzyme is in a specific conformational state offers a paradigm shift in designing the next generation small molecule kinase inhibitors. The current work showcases an extensive and exhaustive array of in vitro biochemical and biophysical tools and techniques deployed along with structural biology efforts of inhibitor-bound kinase complexes to characterize and confirm the cryptic allosteric binding pocket and docking mode of the small molecule actives identified for hTrkA. Specifically, assays were designed and implemented to lock the kinase in a predominantly active or inactive conformation and the effect of the kinase inhibitor probed to understand the hTrkA binding and hTrkB selectivity. The current outcome suggests that inhibitors with a fast association rate take advantage of the inactive protein conformation and lock the kinase state by also exhibiting a slow off-rate. This in turn shifts the inactive/active state protein conformational equilibrium cycle, affecting the subsequent downstream signaling.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/antagonistas & inibidores , Regulação Alostérica , Animais , Simulação por Computador , Humanos , Ligantes , Neuritos , Células PC12 , Inibidores de Proteínas Quinases/metabolismo , Ratos , Receptor trkA/metabolismo
2.
J Med Chem ; 61(3): 1130-1152, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29298069

RESUMO

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Ciclobutanos/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Ciclobutanos/química , Ciclobutanos/farmacocinética , Ciclobutanos/uso terapêutico , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Janus Quinase 1/química , Janus Quinase 2/antagonistas & inibidores , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/química , Pirróis/farmacocinética , Pirróis/uso terapêutico , Ratos , Especificidade por Substrato , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Distribuição Tecidual
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