1,975
Views
0
CrossRef citations to date
0
Altmetric
Brief Report

High-throughput discovery of novel small-molecule inhibitors of acid Ceramidase

, ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 343-348 | Received 03 Oct 2022, Accepted 13 Nov 2022, Published online: 15 Dec 2022

References

  • Hannun YA, Obeid LM. The ceramide -centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem 2002;277:25847–50.
  • MacEyka M, Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature 2014;510:58–67.
  • Obeid LM, Linardic CM, Karolak L, Hannun YA. Programmed cell-death is mediated by ceramide. Clin Res 1993;41:A240.
  • Nganga R, Oleinik N, Ogretmen B. Mechanisms of ceramide-dependent cancer cell death. Adv Cancer Res 2018;140:1–25.
  • Filippov V, Song MA, Zhang K, et al. Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J Alzheimers Dis 2012;29:537–47.
  • Turpin-Nolan SM, Brüning JC. The role of ceramides in metabolic disorders: when size and localization matters. Nat Rev Endocrinol 2020;16:224–33.
  • Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004;4:604–16.
  • Riboni L, Campanella R, Bassi R, et al. Ceramide levels are inversely associated with malignant progression of human glial tumors. Glia 2002;39(2):105–13.
  • Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta Mol Cell Biol Lipids 2008;1781:424–34.
  • García-Barros M, Coant N, Kawamori T, et al. Role of neutral ceramidase in colon cancer. FASEB J 2016;30:4159–71.
  • Yin Y, Xu M, Gao J, Li M. Alkaline ceramidase 3 promotes growth of hepatocellular carcinoma cells via regulating S1P/S1PR2/PI3K/AKT signaling. Pathol Res Pract 2018;214:1381–7.
  • Chen C, Yin Y, Li C, et al. ACER3 supports development of acute myeloid leukemia. Biochem Biophys Res Commun 2016;478:33–8.
  • Saad AF, Meacham WD, Bai A, et al. The functional effects of acid ceramidase overexpression in prostate cancer progression and resistance to chemotherapy. Cancer Biol Ther 2007;6:1455–60.
  • Realini N, Solorzano C, Pagliuca C, et al. Discovery of highly potent acid ceramidase inhibitors with in vitro tumor chemosensitizing activity. Sci Rep 2013;3:1035.
  • Mehta S, Blackinton D, Omar I, et al. Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line. Cancer Chemother Pharmacol 2000;46:85–92.
  • Doan NB, Alhajala H, Al-Gizawiy MM, et al. Acid ceramidase and its inhibitors: a de novo drug target and a new class of drugs for killing glioblastoma cancer stem cells with high efficiency. Oncotarget 2017;8:112662–74.
  • Bedia C, Casas J, Andrieu-Abadie N, et al. Acid ceramidase expression modulates the sensitivity of A375 melanoma cells to dacarbazine. J Biol Chem 2011;286:28200–9.
  • Mahdy AEM, Cheng JC, Li J, et al. Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer. Mol Ther 2009;17:430–8.
  • Gouazé-Andersson V, Flowers M, Karimi R, et al. Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. Prostate 2011;71:1064–73.
  • Saied EM, Arenz C. Inhibitors of ceramidases. Chem Phys Lipids 2016;197:60–68.
  • Pizzirani D, Bach A, Realini N, et al. Benzoxazolone carboxamides: potent and systemically active inhibitors of intracellular acid ceramidase. Angew Chemie - Int Ed. 2015;54:485–9.
  • Bach A, Pizzirani D, Realini N, et al. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: synthesis and structure-activity relationship (SAR) studies. J Med Chem. 2015;58:9258–72.
  • Di Martino S, Tardia P, Cilibrasi V, et al. Lead optimization of benzoxazolone carboxamides as orally bioavailable and CNS penetrant acid ceramidase inhibitors. J Med Chem 2020;63:3634–64.
  • Casasampere M, Izquierdo E, Casas J, et al. Click and count: specific detection of acid ceramidase activity in live cells. Chem Sci 2020;11:13044–51.
  • Bedia C, Casas J, Garcia V, et al. Synthesis of a novel ceramide analogue and its use in a high-throughput fluorogenic assay for ceramidases. Chembiochem 2007;8:642–8.
  • Bielsa N, Casasampere M, Aseeri M, et al. Discovery of deoxyceramide analogs as highly selective ACER3 inhibitors in live cells. Eur J Med Chem 2021;216:113296.
  • Ordóñez YF, Abad JL, Aseeri M, et al. Activity-based imaging of acid ceramidase in living cells. J Am Chem Soc 2019;141:7736–42.
  • Otsuka Y, Airola MV, Choi YM, et al. Identification of small-molecule inhibitors of neutral ceramidase (NCDase) via target-based high-throughput screening. SLAS Discov 2021;26:113–21.
  • Healey RD, Saied EM, Cong X, et al. Discovery and mechanism of action of small molecule inhibitors of ceramidases**. Angew Chemie Int Ed 2022;61:e202109967.
  • Casasampere M, Bielsa N, Riba D, et al. New fluorogenic probes for neutral and alkaline ceramidases. J Lipid Res 2019;60:1174–81.
  • He X, Li C, Park J, Dagan A, et al. A fluorescent-based high performance liquid chromarographic assay to determine acid ceramidase activity. Anal Biochem 1999;274:264–9.