ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

Q2 · MEDICINE

Article

Author: Kerppola, Tom Klaus ; Burns, Veronica Elizabeth

AbstractBackground and PurposeTo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR‐101 (PD132301‐02).Experimental ApproachWe compared the effects of ATR‐101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC‐derived cell lines. We examined the effects of these compounds in combination with methyl‐β‐cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds.Key ResultsATR‐101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC‐derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl‐β‐cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR‐101. ATR‐101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR‐101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR‐101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR‐101. ATR‐101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation.Conclusions and ImplicationsInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR‐101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.

01 May 1994·Journal of Medicinal ChemistryQ1 · MEDICINE

Inhibitors of Acyl-CoA:Cholesterol Acyltransferase (ACAT). 7. Development of a Series of Substituted N-Phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with Enhanced Hypocholesterolemic Activity

Q1 · MEDICINE

Article

Author: Trivedi, Bharat K. ; Holmes, Ann ; Stanfield, Richard L. ; Hamelehle, Katherine L. ; Bousley, Richard F. ; Purchase, Terri Stoeber ; Essenburg, Arnold D. ; Krause, Brian R. ; Augelli-Szafran, Corinne E.

We recently described our initial structure-activity relationship (SAR) studies on a series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). From this series of analogs, compound 1 (PD 129337) was identified as a potent inhibitor of ACAT with an IC50 value of 17 nM. It was also shown to dose-dependently lower plasma cholesterol in cholesterol-fed rats. However, further investigation led to the suggestion that this compound was poorly absorbed, due to a lack of efficacy when administered by gavage in an aqueous vehicle. To overcome this deficiency, we continued our SAR study on this novel series of ACAT inhibitors using an acute in vivo screen in which the compounds are administered to rats in an aqueous, CMC/Tween suspension vehicle. Modification of the N'-phenyl moiety by incorporating functional groups which were amenable to forming salts and/or polar groups to reduce lipophilicity led to the identification of several inhibitors which displayed excellent efficacy employing this protocol. Overall, substitution on the phenyl ring in the ortho, meta, or para positions led to inhibitors with only a slight decrease in potency in vitro compared to the parent unsubstituted compound. Bulkier groups in the para position tended to lower the ACAT inhibitory activity in vitro. Polar groups, such as carboxyl (33,34), lowered in vitro activity significantly, suggesting that polar-ionic interactions are disfavored for the enzyme activity. From this series, compound 28 was evaluated further in secondary in vivo screens. In a chronic cholesterol-fed rat model of hypercholesterolemia, compound 28 dose-dependently reduced nonHDL cholesterol and significantly elevated HDL cholesterol. It showed significantly greater aqueous solubility than the parent compound 1. However, it was shown to cause adrenal toxicity in guinea pigs. This led us to design a series of homologs (44-51) with increased basicity and lower lipophilicity. Some of these compounds were more potent ACAT inhibitors in vitro and demonstrated excellent hypocholesterolemic activity in vivo. Interestingly, compound 45, unlike 28, did not produce adrenal toxicity in guinea pigs and demonstrated excellent lipid-modulating activity in the chronic model of preestablished dyslipidemia in rats.

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Discovery	US	Parke-Davis & Co. Ltd.	-
Hypercholesterolemia	Discovery	US	Parke-Davis & Co. Ltd.	-

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