RESUMO
We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Animais , Humanos , Camundongos , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
Assuntos
Química Farmacêutica/métodos , Intestinos/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Absorção , Trifosfato de Adenosina/química , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Agregação Plaquetária , Ratos , Receptores Proteína Tirosina Quinases/químicaRESUMO
A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.