RESUMO
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein-protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6-corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a, we identified a novel BCL6-corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay [ELISA] IC50=0.10µM, cell-based mammalian two-hybrid [M2H] assay IC50=0.72µM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies.
Assuntos
Desenho de Fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Aminas/química , Aminas/metabolismo , Aminas/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Simulação de Dinâmica Molecular , Ligação Proteica , Mapas de Interação de Proteínas , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Técnicas do Sistema de Duplo-HíbridoRESUMO
With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2'-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
Assuntos
ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Piperidinas/química , Potássio/metabolismo , Inibidores da Bomba de Prótons/síntese química , Compostos de Espiro/química , Administração Intravenosa , Animais , Área Sob a Curva , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/química , Meia-Vida , Histamina/toxicidade , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Naftalenos/química , Piperidinas/síntese química , Piperidinas/farmacocinética , Potássio/química , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/farmacocinética , Curva ROC , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives were designed and synthesized based on our docking model as potassium-competitive acid blockers (P-CABs). Molecular modeling of these derivatives led us to introduce a substituent at the 1-position to access two lipophilic sites and polar residues. We identified potent P-CABs that exhibit excellent inhibitory activity in vitro and in vivo. These results indicate that the 1H-pyrrolo[2,3-c]pyridine-7-amine derivatives are promising lead compounds as P-CABs.
Assuntos
Modelos Moleculares , Potássio , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/farmacologia , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Ácido Gástrico/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Histamina/farmacologia , Masculino , Inibidores da Bomba de Prótons/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
With the aim of discovering a selective kinase inhibitor targeting pan-RAF kinase inhibition, we designed novel 1,3-benzothiazole derivatives based on our thiazolo[5,4-b]pyridine class RAF/VEGFR2 inhibitor 1 and developed a regioselective cyclization methodology for the C-7-substituted 1,3-benzothiazole scaffold utilizing meta-substituted anilines. Eventually, we selected 7-cyano derivative 8B (TAK-632) as a development candidate and confirmed its binding mode by cocrystal structure with BRAF. Accommodation of the 7-cyano group into the BRAF-selectivity pocket and the 3-(trifluoromethyl)phenyl acetamide moiety into the hydrophobic back pocket of BRAF in the DFG-out conformation contributed to enhanced RAF potency and selectivity vs VEGFR2. Reflecting its potent pan-RAF inhibition and slow off-rate profile, 8B demonstrated significant cellular activity against mutated BRAF or mutated NRAS cancer cell lines. Furthermore, in both A375 (BRAF(V600E)) and HMVII (NRAS(Q61K)) xenograft models in rats, 8B demonstrated regressive antitumor efficacy by twice daily, 14-day repetitive administration without significant body weight loss.