BSPED2018 Oral Communications Oral Communications 4 (8 abstracts)
Identification and characterisation of a small-molecule ACTH receptor/Melanocortin-2-receptor antagonist
Li Chan 1 , Mashal Hussain 1 , Rachel Forfar 2 , Puneet Khurana 2 , Jennifer Cook 2 , Steve Lewis 2 , Ed McIver 2 , Jeff Jerman 2 , Debra Taylor 2 & Adrian Clark 1
1William Harvey Research Institute, London, UK; 2LifeArc, Stevenage, UK.
The overproduction of ACTH, in conditions such as Congenital Adrenal Hyperplasia (CAH) leads to significant morbidity. Current treatment with glucocorticoids does not adequately suppress plasma ACTH, resulting in excess adrenal androgen production. At present, there is no effective medical treatment that would directly block ACTH action. Such a therapy, especially one that can be orally administered, would be of great clinical value allowing a ‘block and replace’ treatment strategy. ACTH acts on a highly selective receptor, the ACTH-receptor, also known as the melanocortin-2-receptor (MC2R). ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic strategy in the treatment of CAH. Here we describe the identification of a specific small-molecule MC2R antagonist. We screened ~200,000 low molecular weight drug-like compounds from the Medical Research Council Technology library for MC2R antagonist activity using a high throughput cAMP homogeneous time-resolved fluorescence assay in CHO cells stably co-expressing human MC2R and its accessory protein MRAP. ~700 unique hits with MC2R antagonist properties were counter-screened against the β2-adrenergic receptor, another Gs-coupled GPCR. 208 compounds capable of inhibiting activation of MC2R by 50% or more, with little effect on β2 activity, were profiled further. Hit confirmation and dose-response analysis on these MC2R compounds revealed four novel lead compounds. 10 μM of these compounds caused a log shift in the half maximal effective concentration (EC50) of ACTH. Schild plot analyses and determination of antagonist affinity (pA2), suggest a competitive nature of antagonism (pA2 5.872-5.737). Using mouse Y-1 adrenocortical cells, endogenously expressing murine MC2R and MRAP, we demonstrated that one of the four lead molecules, Compound 4, could significantly inhibit cell signalling and steroidogenesis (lowering progesterone release from 400 pg/ml to 150 pg/ml). No antagonistic activity of Compound 4 was seen with the other four melanocortin receptor family members when stimulated with α-MSH or ACTH, highlighting the specificity of Compound 4 for the MC2R. Studies are now underway to study the effectiveness of Compound 4 in-vivo.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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