RESUMO
The "Notch-sparing" γ-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of Aß production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan-GSIs, but not by γ-secretase modulators. Furthermore, BMS-708,163 blocks the binding of four different active site-directed GSI photoaffinity probes. We therefore report that this compound acts as a nonselective γ-secretase inhibitor.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Oxidiazóis/farmacologia , Presenilinas/antagonistas & inibidores , Receptores Notch/metabolismo , Sulfonamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Domínio Catalítico , Ensaios Clínicos Fase II como Assunto , Células HeLa , Humanos , Presenilinas/genética , Presenilinas/metabolismo , Ligação Proteica/efeitos dos fármacos , Receptores Notch/genéticaRESUMO
Aß42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aß42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.
