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    • Until recently the mechanism of how

    2022-03-10

    Until recently the mechanism of how GSMs shifted γ-secretase cleavage was poorly understood. Today, building on the sequential cleavage model developed by Ihara and colleagues [14], there is evidence that GSMs act as processivity enhancers, and iGSMs as inhibitors of processivity [120]. At least for APP and Notch, neither acidic, non-acidic GSMs nor iGSMS significantly alter the initial γ-secretase cleavage site [150], [152], [176], [177], but they do appear to primarily alter the subsequent number of processivity cleavage events. For classic GSMs this means that they increase cleavage of Aβ1–42 to Aβ1–38; for many iGSMs, they appear to do the opposite. Although not directly established non-acidic GSMs appear would be proposed to increase processivity of Aβ1–40 and Aβ1–42 to Aβ1–37 and Aβ1–38. The novel triterpenoid GSMs recently described by Satori Pharmaceuticals, are somewhat unusual as they decrease both Aβ1–38 and Aβ1–42 [173], [174]. How this unusual type of modulation occurs is unclear, but could be accounted for either by effect on the substrate product line that is determined by the initial γ-secretase cleavage (i.e. a shift to cleavage that initially generates Aβ1–49) or decreased processivity along the Aβ1–42 product line. If the latter is the case, then an even longer Aβ peptide should accumulate. Notably, for the more well studied GSMs there is clear evidence that these compounds do not alter Notch 1 processing to any great extent [129], [150], [152]. They preserve Notch 1 signaling and thus are thought to be inherently safe. Although it Cinobufagin is almost certain that GSMs will to varying extents modulate cleavage of some other γ-secretase substrates, there is no evidence to date that this will have significant biological impact. GSMs are not likely to alter signaling events mediated by the initial γ-cleavage and subtle shifts in the length of the short Aβ like fragments produced by subsequent γ-cleavages are unlikely to have significant liabilities. There remains some controversy over the binding site of GSMs. Low potency NSAID-based GSMs have been shown to bind substrate [171], [178], [179], whereas more potent acidic GSMs and non-acidic GSMs have been shown to bind PSEN1 or PEN-2 [171], [180], [181], [182]. The target of the triterpenoid natural product has not been established. Notably, there is evidence that the effect of GSMs is substrate selective and that sequences within substrate dramatically influence processivity of γ-secretase [129], [130]. Collectively these binding studies and substrate selective effects of GSMs suggest that there may tripartite interactions between GSM, γ-secretase and substrate that subtly alter processivity perhaps by altering residence time of the substrate within the active site of γ-secretase. Another area of some controversy is whether APP and PS1 mutations influence the potency of GSMs. Though potency of 1st generation GSM were reported to be altered by AD-linked PS1 and APP mutations, other studies with more potent GSMs showed little effect on potency [175], [183].
    Clinical development of GSMs A Phase III study of the NSIAD based GSM Tarenflurbil (R-flurbiprofen) in patients with mild AD showed no benefit on cognitive or functional outcomes [184]. Tarenflurbil is a weak GSM with low CNS penetrance limiting general inferences based on this trial with respect to clinical efficacy of more potent, CNS penetrant GSMs [11], [151], [160], [185]. Many companies and academic groups have ongoing GSM development programs and several more potent GSM have entered early phase clinical trials. TheGSM, CHF5074, based on R-flurbiprofen developed by Chiesi Pharmaceuticals has advanced the furthest in human testing completing a phase II trial [157]. Recent data suggest that while this compound may possess GSM activity it may have a rich pharmacology and may have additional mechanism(s) of action besides altering Aβ42 [186], [187], [188]. One clear challenge in the development of potent GSMs that have been recently reviewed [160], is the balance between liophillicity and potency. Although potency and brain penetration have been dramatically improved in 2nd and 3rd generation GSMs, this has been associated with increases in lipophillicty of the compounds. It has been proposed that this lipophillicity as well as potential glucuronidation of acidic GSMs contributes to what are thought to be off-target, primarily liver toxicities [160].