Part 2. Notch-sparing γ-secretase inhibitors: The study of novel γ-amino naphthyl alcohols.
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ABSTRACT:
SUBMITTER: Wei HX
PROVIDER: S-EPMC8323768 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:γ-Secretase is one of two proteases directly involved in the production of the amyloid β-peptide (Aβ), which is pathogenic in Alzheimer's disease. Inhibition of γ-secretase to suppress the production of Aβ should not block processing of one of its alternative substrates, Notch1 receptors, as interference with Notch1 signaling leads to severe toxic effects. In the course of our studies to identify γ-secretase inhibitors with selectivity for APP over Notch, 1 [3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one] was found to inhibit γ-secretase-mediated Aβ production without interfering with γ-secretase-mediated Notch processing in purified enzyme assays. As 1 is chemically unstable, efforts to increase the stability of this compound led to the identification of 2 [naphthalene-2-carboxylic acid benzyl-isopropyl-amide] which showed similar biological activity to compound 1. Synthesis and evaluation of a series of amide analogs resulted in benzofuranyl amide analogs that showed promising Notch-sparing γ-secretase inhibitory effects. This class of compounds may serve as a novel lead series for further study in the development of γ-secretase inhibitors.
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Project description:In search for novel lead compounds as γ-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-ones (I) were synthesized and evaluated for inhibitory effects on amyloid-β-peptide production and cleavage of the Notch1 receptor mediated by γ-secretase. Selected pyridopyrimidines, such as 1, 8, 9, 10, 11 and 16 are γ-secretase inhibitors that did not have an effect on Notch1 receptor processing.
| S-EPMC8314044 | biostudies-literature
Project description:The numerous processes involved in the etiology of breast cancer such as cell survival, metabolism, proliferation, differentiation, and angiogenesis are currently being elucidated. However, underlying mechanisms that drive breast cancer progression and drug resistance are still poorly understood. As we discuss here in detail, the Notch signaling pathway is an important regulatory component of normal breast development, cell fate of normal breast stem cells, and proliferation and survival of breast cancer initiating cells. Notch exerts a wide range of critical effects through a canonical pathway where it is expressed as a type I membrane precursor heterodimer followed by at least two subsequent cleavages induced by ligand engagement to ultimately release an intracellular form to function as a transcriptional activator. Notch and its ligands are overexpressed in breast cancer, and one method of effectively blocking Notch activity is preventing its cleavage at the cell surface with ?-secretase inhibitors. In the context of Notch signaling, the application of clinically relevant anti-Notch drugs in treatment regimens may contribute to novel therapeutic interventions and promote more effective clinical response in women with breast cancer.
| S-EPMC3726525 | biostudies-literature
Project description:Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.
| S-EPMC9180633 | biostudies-literature
Project description:Activating mutations in the NOTCH1 gene are found in over 50 % of T-ALL cases. Since Notch signaling contributes to the leukemia cell survival and growth, targeting Notch signaling using ?-secretase inhibitors (GSI) has been proposed as a molecularly targeted therapy for the treatment of T-ALL. However, not all T-ALL with NOTCH1 activating mutations respond to GSI treatment. We examined whether GSI could enhance the cytotoxic effect of anti-leukemic agents in the GSI-resistant T-ALL cells although GSI does not have anti-tumor effect as a single agent. GSI significantly increased cell death induced by Vincristine (VCR) but not other anti-leukemic drugs (Methotrexate, Asparaginase, and Cytarabine). The GSI effect in enhancing VCR efficacy was not the result of inhibition of Notch signaling. GSI augmented VCR-induced mitotic arrest, followed by apoptosis. GSI accelerated VCR-triggered loss of mitochondrial membrane potential and caspase-mediated apoptosis. Our finding suggests that GSI has other functions besides inhibiting Notch signaling in T-ALL and incorporating GSI into the conventional regimen containing VCR may offer therapeutic advantage by potentiating VCR treatment in leukemia patients.
| S-EPMC4198427 | biostudies-literature
Project description:gamma-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.
| S-EPMC2118656 | biostudies-literature
Project description:Lung cancer is the leading cause of cancer-related deaths among men and women. ?-Secretase inhibitors, a class of small-molecule compounds that target the Notch pathway, have been tested to treat non-small-cell lung cancer (NSCLC) in preclinical and clinical trials. Although ?-secretase inhibitors elicit a response in some tumors as single agents and sensitize NSCLC to cytotoxic and targeted therapies, they have not yet been approved for NSCLC therapy. We discuss our recently published preclinical study using the ?-secretase inhibitor AL101, formerly BMS906024, on cell lines and PDX models of NSCLC, primarily lung adenocarcinoma. We propose that Notch pathway mutations may not be the most suitable biomarker for predicting NSCLC response to ?-secretase inhibitors. ?-Secretases have over 100 known ?-secretase cleavage substrates. Many of the ?-secretase substrates are directly involved in carcinogenesis or tumor progression, and are ideal candidates to be the "on-target" biomarkers for ?-secretase inhibitors. We propose the need to systematically test the ?-secretase and other targets as potential biomarkers for sensitivity before continuing clinical trials. Now that we have entered the postgenome/transcriptome era, this goal is easily attainable. Discovery of the biomarker(s) that predict sensitivity to ?-secretase inhibitors would guide selection of the responder population that is most likely to benefit and move the compounds closer to approval for therapeutic use in NSCLC.
| S-EPMC6295228 | biostudies-literature
Project description:Over two decades, γ-secretase has been the target for extensive therapeutic development due to its pivotal role in pathogenesis of Alzheimer's disease and cancer. However, it has proven to be a challenging task owing to its large set of substrates and our limited understanding of the enzyme's structural and mechanistic features. The scientific community is taking bigger strides towards solving this puzzle with recent advancement in techniques like cryogenic electron microscopy (cryo-EM) and photo-affinity labelling (PAL). This review highlights the significance of the PAL technique with multiple examples of photo-probes developed from γ-secretase inhibitors and modulators. The binding of these probes into active and/or allosteric sites of the enzyme has provided crucial information on the γ-secretase complex and improved our mechanistic understanding of this protease. Combining the knowledge of function and regulation of γ-secretase will be a decisive factor in developing novel γ-secretase modulators and biological therapeutics.
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Project description:Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.NEW & NOTEWORTHY Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.
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Project description:Sensorineural hearing loss is prevalent within society affecting the quality of life of 460 million worldwide. In the majority of cases, this is due to insult or degeneration of mechanosensory hair cells in the cochlea. In adult mammals, hair cell loss is irreversible as sensory cells are not replaced spontaneously. Genetic inhibition of Notch signaling had been shown to induce hair cell formation by transdifferentiation of supporting cells in young postnatal rodents and provided an impetus for targeting Notch pathway with small molecule inhibitors for hearing restoration. Here, the oto-regenerative potential of different γ-secretase inhibitors (GSIs) was evaluated in complementary assay models, including cell lines, organotypic cultures of the organ of Corti and cochlear organoids to characterize two novel GSIs (CPD3 and CPD8). GSI-treatment induced hair cell gene expression in all these models and was effective in increasing hair cell numbers, in particular outer hair cells, both in baseline conditions and in response to ototoxic damage. Hair cells were generated from transdifferentiation of supporting cells. Similar findings were obtained in cochlear organoid cultures, used for the first time to probe regeneration following sisomicin-induced damage. Finally, effective absorption of a novel GSI through the round window membrane and hair cell induction was attained in a whole cochlea culture model and in vivo pharmacokinetic comparisons of transtympanic delivery of GSIs and different vehicle formulations were successfully conducted in guinea pigs. This preclinical evaluation of targeting Notch signaling with novel GSIs illustrates methods of characterization for hearing restoration molecules, enabling translation to more complex animal studies and clinical research.
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