Genetic and biological studies provide strong evidence that the deposition of amyloid-β peptide (Aβ) contributes to the etiology of Alzheimer's disease (AD). Thus, drugs that regulate the brain Aβ levels could provide effective disease-modifying therapy for AD. Aβ is generated from amyloid-β precursor protein (APP) by β- and γ-secretases. Several γ-secretase inhibitors have been developed as AD therapeutics. However, simple inhibition of γ-secretase would have adverse consequences, as γ-secretase is involved in several signaling pathways including Notch signaling. In 2010, the development of semagacestat, a γ-secretase inhibitor, was halted. Preliminary results from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, semagacestat treatment was associated with an increased risk of skin cancer. Thus, alternative compounds that indirectly modulate γ-secretase activity without affecting Notch are attracting attention. However, molecular mechanism of these compounds still remains unclear. To develop therapeutics with superior specificity and high potency for AD, we have been analyzing the mode of actions of known compounds, structure-and-function relationship of the γ-secretase complex and possible rational design of γ-secretase inhibitors and modulators using chemical biology.
