ArticlePharmaceutical research2020
In Vitro Evaluation of Clinical Candidates of γ-Secretase Inhibitors: Effects on Notch Inhibition and Promoting Beige Adipogenesis and Mitochondrial Biogenesis.
Article in Pharmaceutical research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- High throughput and targeted screens for prepilin peptidase inhibitors do not identify common inhibitors of eukaryotic gamma-secretase.Expert opinion on drug discovery · 2023Article
- Mitochondrial Energy Metabolism in the Regulation of Thermogenic Brown Fats and Human Metabolic Diseases.International journal of molecular sciences · 2023Review
- Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations-NOTCH1, SF3B1, MYD88, BIRC3.Journal of clinical medicine · 2021Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
purposeInhibition of Notch signaling has been recently demonstrated to promote beige adipocyte biogenesis. However, most γ-secretase inhibitors (GSIs) used to achieve pharmacological inhibition of Notch signaling are at the basic research or preclinical stage, limiting the translation of fundamental findings into clinical practice. This present study aimed to evaluate the potential of several clinical candidates of GSIs as browning agents for the treatment of obesity.
methodsSeven GSIs that are clinical candidates for the treatment of Alzheimer's disease or cancer were selected and their impacts on Notch inhibition as well as promoting beige biogenesis were compared using in vitro culture of 3T3-L1 preadipocytes.
resultsFour compounds (i.e.RO4929097, PF-03084014, LY3039478, and BMS-906024) that efficiently inhibited the expression of Notch target genes in 3T3-L1 preadipocytes were identified. Moreover, these compounds were optimized for dose-dependent effects at three gradient concentrations (0.5, 1, and 10 μM) to promote beige adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes without causing severe cytotoxicity.
conclusionsOur findings not only highlight the potential of cross-therapeutic application of these GSIs for obesity treatment via inhibition of γ-secretase-mediated processing of Notch signaling, but also provide important experimental evidence to support further design and development of clinically translatable Notch-inhibiting drug delivery systems.
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