RESUMO
A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
Assuntos
Inibidores Enzimáticos/química , Modelos Moleculares , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/química , Relação Quantitativa Estrutura-Atividade , Adenina/química , Trifosfato de Adenosina/química , Compostos de Anilina/química , Sítios de Ligação , Ensaios de Triagem em Larga Escala , Indazóis/química , Indóis/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase , Ligação Proteica , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/química , Piridinas/química , Pirimidinas/química , Bibliotecas de Moléculas PequenasRESUMO
The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.
Assuntos
Química Farmacêutica/métodos , Quinase I-kappa B/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Trifosfato de Adenosina/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Demonstration that IkappaB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-kappaB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC(50) = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-alpha, IL-6, and IL-8 with an IC(50) = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i.p., b.i.d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i.p., b.i.d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i.p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i.p., b.i.d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i.p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.
