RESUMO
Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins ("its clients"). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. It has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from oncology to neurodegenerative and infectious diseases. The most promising inhibitors reported to date inhibit the ATPase activity by binding to the N-terminal ATP pocket. Radicicol, a member of the resorcylic acid lactones (RALs), represents an important pharmacophore to this end. Efforts towards the development of this pharmacophore and its SAR are reviewed herein.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Macrolídeos/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/química , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Proteínas de Choque Térmico HSP90/química , Humanos , Macrolídeos/síntese química , Macrolídeos/química , Relação Estrutura-AtividadeRESUMO
Pochoximes are potent inhibitors of heat shock protein 90 (HSP90) based on the radicicol pharmacophores. Herein we present a pharmacokinetics and pharmacodynamics evaluation of this compound series as well as a phosphate prodrug strategy to facilitate formulation and improve oral bioavailability.