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Identification of a novel class of cortisol biosynthesis inhibitors and its implications in a therapeutic strategy for hypercortisolism

Title
Identification of a novel class of cortisol biosynthesis inhibitors and its implications in a therapeutic strategy for hypercortisolism
Authors
Kim S.H.Son G.H.Seok J.Y.Chun S.K.Yun H.Jang J.Suh Y.-G.Kim K.Jung J.-W.Chung S.
Ewha Authors
정수영
SCOPUS Author ID
정수영scopus
Issue Date
2023
Journal Title
Life Sciences
ISSN
2432-3205JCR Link
Citation
Life Sciences vol. 325
Keywords
Adrenal glandBenzimidazolylureasCholesterolCorticosteroidsCortisolSteroidogenesis
Publisher
Elsevier Inc.
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Aims: Dysregulation of adrenocortical steroid (corticosteroids) biosynthesis leads to pathological conditions such as Cushing's syndrome. Although several classes of steroid biosynthesis inhibitors have been developed to treat cortisol overproduction, limitations such as insufficient efficacy, adverse effects, and/or tolerability still remain. The present study aimed to develop a new class of small molecules that inhibit cortisol production, and investigated their putative modes of action. Main methods: We screened an in-house chemical library with drug-like chemical scaffolds using human adrenocortical NCI-H295R cells. We then evaluated and validated the effects of the selected compounds at multiple regulatory steps of the adrenal steroidogenic pathway. Finally, genome-wide RNA expression analysis coupled with gene enrichment analysis was conducted to infer possible action mechanisms. Key findings: A subset of benzimidazolylurea derivatives, including a representative compound (designated as CJ28), inhibited both basal and stimulated production of cortisol and related intermediate steroids. CJ28 attenuated the mRNA expression of multiple genes involved in steroidogenesis and cholesterol biosynthesis. Furthermore, CJ28 significantly attenuated de novo cholesterol biosynthesis, which contributed to its suppression of cortisol production. Significance: We identified a novel chemical scaffold that exerts inhibitory effects on cortisol and cholesterol biosynthesis via coordinated transcriptional silencing of gene expression networks. Our findings also reveal an additional adrenal-directed pharmacological strategy for hypercortisolism involving a combination of inhibitors targeting steroidogenesis and de novo cholesterol biosynthesis. © 2023
DOI
10.1016/j.lfs.2023.121744
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일반대학원 > 뇌·인지과학과 > Journal papers
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