Inhibitors of Ceramidases

Saied, Essa M.

doi:10.1016/j.chemphyslip.2015.07.009

Cited by 33 publications

(24 citation statements)

References 137 publications

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“…White solid (73 mg, 68% + . 5-Fluoro-2-oxo-N-(4-phenylbutyl)-1,3-benzoxazole-3-carboxamide (11). The reaction was carried out following method A, using 37h (61 mg, 0.398 mmol) and 4-phenylbutyl isocyanate (76.7 mg, 0.075 mL, 0.438 mmol).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…To test this hypothesis, several AC inhibitors have been developed over the past decades. 11 We have recently disclosed a small set of benzoxazolone carboxamides as the first example of systemically active inhibitors of intracellular AC activity. 12 We demonstrated that these molecules covalently inhibit AC through S-acylation of its catalytic nucleophile, Cys-143, with the benzoxazolone ring acting as leaving group.…”

Section: ■ Introductionmentioning

confidence: 99%

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Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies

et al. 2015

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Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity−stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.

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Section: ■ Conclusionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies

et al. 2015

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“…The interaction of this sphingolipid metabolism modulator with PDT‐based antitumor mechanisms extends from boosting direct tumor cell killing pathways to influencing immune system contribution that includes overriding negative effects of major immunoregulatory populations. The advantages of LCL521 over other sphingolipid metabolism‐modulating agents we tested thus far in combination with PDT include its good water solubility, efficient targeted delivery (lysosomotropic properties) and lower systemic toxicity …”

Section: Discussionmentioning

confidence: 99%

“…The advantages of LCL521 over other sphingolipid metabolism-modulating agents we tested thus far in combination with PDT include its good water solubility, efficient targeted delivery (lysosomotropic properties) and lower systemic toxicity. [17][18][19][20]48…”

Section: Discussionmentioning

confidence: 99%

Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy‐generated vaccine

Korbelik

Banáth

Zhang

et al. 2016

Intl Journal of Cancer

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Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill.

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“…Among the enzymes and receptors that metabolize or interact with sphingolipids, most drug development efforts have focused on inhibition of ceramidases, SKs, or S1PRs. Recent reviews discuss the roles and pharmacology of ceramidases in detail (Coant, Sakamoto, Mao, & Hannun, 2017; Saied & Arenz, 2016; Tan, Pearson, Feith, & Loughran, 2017). Additionally, S1PR biology and a diverse set of compounds that modulate S1PR signaling have been well discussed in several recent reviews (Hait & Maiti, 2017; Huwiler & Zangemeister-Wittke, 2017; Juif, Kraehenbuehl & Dingemanse, 2016; Mao-Draayer, Sarazin, Fox, & Schiopu, 2017; Patmanathan, Wang, Yap, Herr, & Paterson, 2017; Pyne, El Buri, Adams, & Pyne, 2017).…”

Section: Potential Drug Targets In the Sphingolipid Metabolism Pathwaymentioning

confidence: 99%

Targeting Sphingosine Kinases for the Treatment of Cancer

Lewis

Voelkel‐Johnson

Smith

2018

Advances in Cancer Research

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Sphingosine kinases (SK1 and SK2) are key, druggable targets within the sphingolipid metabolism pathway that promote tumor growth and pathologic inflammation. A variety of isozyme-selective and dual inhibitors of SK1 and SK2 have been described in the literature, and at least one compound has reached clinical testing in cancer patients. In this chapter, we will review the rationale for targeting SKs and summarize the preclinical and emerging clinical data for ABC294640 as the first-in-class selective inhibitor of SK2.

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Inhibitors of Ceramidases

Cited by 33 publications

References 137 publications

Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies

Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies

Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy‐generated vaccine

Targeting Sphingosine Kinases for the Treatment of Cancer

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