GSIs were shown to effectively decrease A levels at doses

GSIs were shown to effectively decrease Aβ levels at doses close to or higher than their IC50 values in cell culture models. Surprisingly, they also slightly increase Aβ levels at low doses, (significantly below the IC50) also known as “Aβ rise”, due to various mechanisms including inhibition of cellular γ-secretase activity (Barnwell et al., 2014; Burton et al., 2008; Citron et al., 1996; Lanz et al., 2006; Mitani et al., 2012). Particularly, a potent peptidomimetic GSI, semagacestat, increases Aβ42 levels at low doses in H4 Caspase-9, human recombinant protein stably over-expressing an FAD-linked Swedish double mutation and also increases Aβ42 levels in CSF and plasma of treated guinea pigs. These preclinical outcomes recapitulate the biomarker results of semagacestat's clinical trials for AD (Fleisher et al., 2008). Previous studies have shown that PS1 exists in a dynamic equilibrium of different conformational states, characterized by varied proximities between the PS1 NT and CT large cytosolic loop domain (Kuzuya et al., 2016; Maesako et al., 2017; Uemura et al., 2010). Importantly, PS1 subdomain arrangement strongly correlates with the changes in Aβ (42:40) ratios (Kuzuya et al., 2016; Maesako et al., 2017; Uemura et al., 2010; Zoltowska et al., 2017). For example, fenofibrate, an antilipidemic agent that potently increases the Aβ (42:40) ratios (Kukar et al., 2005) leads to shortening of the donor fluorophore lifetime (τ1) and increased FRET efficiency, which indicates a closer proximity of PS1 subdomains, or ‘closing’ of PS1 conformation (Uemura et al., 2010). Alternatively, ibuprofen, a small molecule that belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs) known to decrease the Aβ (42:40) ratios results in “opening” of PS1 conformation (Uemura et al., 2010). Taken together, a pharmacological agent that elicits an “opening” of PS1 conformation should preferentially decrease relative levels of the longer, Aβ42 species and may have potential as a treatment for AD. Consistent with the in vitro and in vivo results showing attenuation of Aβ42, the antibody-based FLIM PS1 conformation assay demonstrate that SGSM-36 induces a conformational shift within the endogenous PS1 molecule toward the “open”, non-pathogenic state (Fig. 4A and B). The FRET data points toward a potential molecular mechanism in which SGSM-36 reduces Aβ (42:40) ratios by instigating a shift in the structure of the enzyme resulting in enhanced proteolytic processing of the substrate.
Introduction Anaplastic large cell lymphoma (ALCL) is an aggressive subtype of non-Hodgkin's lymphoma (NHL) that is derived from CD4+ T cells [1]. Systemic ALCL is classified into two subtypes based on the presence or absence of chromosomal translocations of the anaplastic lymphoma kinase (ALK) gene at the 2p23 locus [2,3]. The t (2;5) (p23;q35) translocation in ALCL encodes for the nucleophosmin-ALK (NPM-ALK) fusion protein [4], which interacts with survival pathways to promote cell proliferation, anti-apoptosis and tumor formation [5,6]. Although many patients with ALCL can obtain complete remission with conventional chemotherapy, relapse still frequently occurs and these patients eventually show poor clinical outcome [7,8]. Recent studies on the pathogenesis of malignant T-cell tumors have identified several mechanisms, including abnormal regulation of cellular apoptosis and proliferation and the dysregulation of a variety of signaling pathways, including extracellular signal-regulating kinase 1/2 (ERK1/2) [9,10], nuclear factor (NF)-κB [11,12], AKT/mTOR [9,13], p38 mitogen-activated protein kinase (p38 MAPK) [14], and c-jun N-terminal kinase (JNK/c-Jun) [15]. The identification of new regimens for the treatment of ALK+ ALCL is critical to improve patient outcome, especially non-chemotherapeutic regimens that specifically target these pathways. Studies have demonstrated that irregular activation of the Notch1 pathway is involved in driving tumorigenesis of various cancers. Notch1 signaling regulates cell proliferation and differentiation, and aberrant Notch1 signaling plays a critical role in cancer progression [16]. The γ-secretase is complex protease that contains several transmembrane domains, a catalytic subunit and accessory subunits [17]. Several studies showed that γ-secretase can activate Notch receptors, and thus the development of γ-secretase inhibitors (GSIs) has attracted increasing interest [18]. Indeed, some reports demonstrated that GSIs can prevent activation of the Notch1 signaling pathway [19]. GSIs have been used to block the progression of Alzheimer's disease [20], and Notch1 inhibition by GSIs can be effective in cancers such as hepatocellular carcinoma, gastric cancer, neuroblastoma and others [21]. Moreover, GSIs have shown efficacy against diffuse large B cell lymphoma and mantle cell lymphoma [22]. In NHL, including ALK+ ALCL, GSIs can inhibit proliferation in vitro and induce apoptosis, accompanied with downregulation of cyclin D1, Bcl-xL and XIAP [23]. However, GSIs can cause toxic side effects, including inflammation and gastrointestinal issues [24].