SUN-432 Optimizing Binding Kinetics to Develop Insurmountable MC2 Receptor Antagonists for the Treatment of Congenital Adrenal Hyperplasia

Abstract Disclosure: L. Malet Sanz: OMass Therapeutics. M. Soave: OMass Therapeutics. K. Sengmany: OMass Therapeutics. U.R. Wilcox: OMass Therapeutics. M. Musgaard: OMass Therapeutics. K. Gherbi: OMass Therapeutics. M. Silva: None. A. Jazayeri: OMass Therapeutics. D. Smith: OMass Therapeutics. J. Roffey: OMass Therapeutics. S.C. Griffen: OMass Therapeutics. S.J. Charlton: OMass Therapeutics. Congenital adrenal hyperplasia (CAH) is a collection of genetic disorders characterized by an inability to synthesize cortisol. The resulting loss of cortisol-driven negative feedback causes excess diurnal adrenocorticotropic hormone (ACTH) secretion by the pituitary gland (especially in the morning). Excess ACTH induces adrenal hyperplasia and androgen overproduction, leading to virilisation and early onset puberty. ACTH is the selective agonist for the melanocortin type 2 receptor (MC2R)[1], therefore an MC2R antagonist represents a promising CAH therapeutic agent. The morning surge of ACTH in CAH could outcompete a rapidly equilibrating MC2R antagonist, such as Atumelnant[2,3]. Therefore, we have optimized binding kinetics to develop insurmountable MC2R small molecule antagonists with long residence times to treat the pathophysiological actions of excess ACTH in CAH. We used a model of competitive kinetic binding to determine the residence times (τ) and Ki values of compounds at the human and rat MC2Rs in vitro. Optimizing compounds to obtain longer residence times translated into pharmacological insurmountability following acute challenge of human MC2R with ACTH 1-24 in an in vitro cellular assay, with significant reductions in ACTH 1-24 Emax. An acute rat pharmacodynamic model was used to explore the effect of MC2R antagonism on the production of corticosterone, the dominant glucocorticoid in rats. Oral administration of MC2R antagonists caused a significant reduction in corticosterone produced by 1µg/kg ACTH 1-24 IV bolus in Sprague-Dawley (SD) rats. Moreover, longer residence times measured in vitro translated well into higher efficacy in vivo. Efficacy differences between compounds were the most pronounced at the early timepoints. Combining multiple studies with a stronger acute agonist challenge (10µg/kg ACTH 1-24) allowed for concentration-response relationships to obtain IC50 values for corticosterone inhibition. In a 7-day pharmacodynamic model, SD rats were implanted with a minipump which continually secreted ACTH 1-24 (100µg/kg/day). Compounds reduced plasma corticosterone, restored normal bodyweight gain over the 7 days, as well as protecting against ACTH 1-24-induced adrenal hyperplasia. These data show a clear association between the residence time of compounds tested and their efficacy at inhibiting acute agonist challenge in vitro and in vivo. These results strongly support the development of long residence time antagonists to ensure inhibition of the MC2R during the ACTH surge seen in CAH. References: [1] Novoselova et al.,2019,Endocr. Connect.8, R122-R130 [2] Kim et al.,2024,ACS Med. Chem. Lett.,15(4), 478-85 [3] Kusnetzow et al., 2019, J.E.S., 3, SAT-364 Presentation: Sunday, July 13, 2025