Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Winterton, Sarah E.; Capota, Emanuela; Wang, Xiaoyu; Mallipeddi, Prema L.; Williams, Noelle S.; Posner, Bruce A.; Nijhawan, Deepak; Ready, Joseph M.

doi:10.1021/acs.jmedchem.8b00052

Cited by 22 publications

(19 citation statements)

References 33 publications

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“…SCD1 activity is crucial for the production of sebum, and several abnormalities that result from dysfunction of the sebaceous glands have been observed in mice that are treated with SCD1 inhibitors. However, the recent discovery of metabolically activated SCD1 inhibitors [94,95] sheds new light on the possibility of the clinical use of these compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Further analysis showed that SW208108 is a prodrug that is irreversibly demethylated by cytochrome P450 family 4 subfamily F member 11 (CYP4F11) to dMe-SW208108. This reaction revealed a phenol group that forms covalent adducts with SCD1 [94,95]. Cytochromes of the P450 family (CYP) are frequently expressed in lung epithelial and lung cancer cells to neutralize toxic compounds [182,183].…”

Section: Perspectives Of Scd1 Inhibitors In Anticancer Therapymentioning

confidence: 99%

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Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

Tracz-Gaszewska

Dobrzyń

2019

Cancers

155

149

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A distinctive feature of cancer cells of various origins involves alterations of the composition of lipids, with significant enrichment in monounsaturated fatty acids. These molecules, in addition to being structural components of newly formed cell membranes of intensely proliferating cancer cells, support tumorigenic signaling. An increase in the expression of stearoyl-CoA desaturase 1 (SCD1), the enzyme that converts saturated fatty acids to ∆9-monounsaturated fatty acids, has been observed in a wide range of cancer cells, and this increase is correlated with cancer aggressiveness and poor outcomes for patients. Studies have demonstrated the involvement of SCD1 in the promotion of cancer cell proliferation, migration, metastasis, and tumor growth. Many studies have reported a role for this lipogenic factor in maintaining the characteristics of cancer stem cells (i.e., the population of cells that contributes to cancer progression and resistance to chemotherapy). Importantly, both the products of SCD1 activity and its direct impact on tumorigenic pathways have been demonstrated. Based on these findings, SCD1 appears to be a significant player in the development of malignant disease and may be a promising target for anticancer therapy. Numerous chemical compounds that exert inhibitory effects on SCD1 have been developed and preclinically tested. The present review summarizes our current knowledge of the ways in which SCD1 contributes to the progression of cancer and discusses opportunities and challenges of using SCD1 inhibitors for the treatment of cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Perspectives Of Scd1 Inhibitors In Anticancer Therapymentioning

confidence: 99%

Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

Tracz-Gaszewska

Dobrzyń

2019

Cancers

155

149

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“…Indeed, since the activity of SCD1 is critical for the production of sebum by the sebaceous glands, its inhibition leads to the atrophy of sebocytes, consequently causing eye dryness, hair loss and skin dryness [ 115 , 116 ]. However, new SCD1 inhibitors administrable as “pro-drugs”, have recently been developed [ 117 , 118 ]. Since sebocytes, unlike other cell types, are unable to activate the prodrugs into “active drugs” (irreversible steroyl-CoA inhibitors), these inhibitors may offer the opportunity to inhibit SCD1 more specifically in tumor cells, overcoming the side effects.…”

Section: Targeting Scd1 and Autophagy: Clinical Implicationsmentioning

confidence: 99%

SCD1, autophagy and cancer: implications for therapy

Ascenzi

Vitis

Maugeri‐Saccà

et al. 2021

J Exp Clin Cancer Res

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Background Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid metabolism and autophagy has been uncovered. Methods This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes. Results Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected. Conclusion Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.

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“…Nitroalkenes 4 a , [23] 4 b , [24] 4 c , [25] 4 d , [26] 4 e [27] and 4 g , [28] were synthesized according to literature procedures.…”

Section: Methodsmentioning

confidence: 99%

Sequential Formal [4+1]‐Cycloaddition, C−H Functionalization and Suzuki–Miyaura Cross‐Coupling for the Synthesis of Trisubstituted Isoxazolines

et al. 2021

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Suzuki–Miyaura cross‐coupling reaction of 3‐bromomethyl isoxazolines with arylboronic acids was suggested as final C−C bond forming step in convenient diastereoselective route to trisubstituted isoxazolines. The required bromides were readily available from nitroalkenes and sulfonium ylides through an efficient sequence of formal [4+1]‐cycloaddition and C−H functionalization of intermediate isoxazoline N‐oxides. The synthetic utility of the obtained isoxazolines was demonstrated by their conversion into valuable products such as hydroxy ketone, pyrrolidinone, etc.

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Discovery of Cytochrome P450 4F11 Activated Inhibitors of Stearoyl Coenzyme A Desaturase

Cited by 22 publications

References 33 publications

Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer

SCD1, autophagy and cancer: implications for therapy

Sequential Formal [4+1]‐Cycloaddition, C−H Functionalization and Suzuki–Miyaura Cross‐Coupling for the Synthesis of Trisubstituted Isoxazolines

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