Atumelnant

Cushing's disease is a rare endocrine disorder characterized by hypercortisolism. Chronic elevated cortisol levels can lead to dysfunction or complications in multiple organs of systems, including cardiovascular, glucose, and bone metabolism, severely impacting patients' quality of life and posing life-threatening risks. Surgery is the first-line treatment for Cushing's disease. However, in cases of delayed diagnosis, surgical contraindications, or suboptimal surgical outcomes, pharmacological therapy is often required. Currently, three categories of medications are commonly used: 1) Drugs targeting somatostatin and/or dopamine receptors to inhibit pituitary adrenocorticotropic hormone (ACTH) synthesis (e.g., pasireotide, cabergoline); 2) drugs targeting adrenal cortex-related receptors to suppress steroid synthesis (e.g., ketoconazole, metyrapone, mitotane, and osilodrostat); 3) drugs acting on glucocorticoid receptors (e.g., mifepristone). Research on pharmacological treatments for Cushing's disease is ongoing, with new drugs such as seliciclib, CRN04894, fimepinostat, vorinostat, and SPI-62 currently in phase II clinical trial. The development of novel drugs holds promise for more precise and effective treatment for Cushing's disease patients.

Adrenocorticotropic hormone (ACTH) is secreted from the pituitary gland and selectively activates the melanocortin type 2 receptor (MC2R) in the adrenal glands, where it modulates steroidal hormone (e.g., cortisol) synthesis and secretion. Excess ACTH contributes to the pathophysiology of Cushing’s disease (CD), ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH). ACTH‐secreting tumors cause CD (in pituitary) and EAS (outside pituitary) and lead to hypercortisolemia and various metabolic comorbidities. CAH is caused by inactivating mutations in adrenal steroid synthesis pathway proteins leading to low levels of cortisol that are insufficient to provide negative feedback on ACTH production. Chronic ACTH elevation can lead to life‐threatening salt wasting and significant virilization. We hypothesize that blocking the ACTH‐MC2R interaction with a selective MC2R antagonist may provide a key new therapeutic option for these patients. We initiated an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2R antagonists suitable for evaluation in clinical trials. Initial assessment consisted of equilibrium radioligand binding competition assays using [ 125 I]ACTH(1‐39) to determine K i and EC 50 shift functional assays using ACTH(1‐24) to determine ΔpEC 50 values. Select compounds were then characterized using a full Schild regression analysis to determine K B values and gain insight into mechanism. There was a strong correlation between the K i and K B values for this class of small molecule. Our efforts identified CRN04894 as a highly potent MC2R antagonist (K i = 2.1 nM, K B = 0.34 nM). The Schild regression data for CRN04894 was consistent with a competitive, orthosteric interaction with ACTH. The individual ACTH dose‐response curves with the addition of different concentrations of CRN04894 showed the same maximum response and slopes near unity, and the Schild plot had a slope not statistically different than unity. Furthermore, CRN04894 did not affect the dissociation rate of [ 125 I]ACTH(1‐39) initiated by a saturating concentration of ACTH(1‐39), also consistent with an orthosteric interaction. Because CRN04894 appeared to bind the orthosteric site on MC2R, it was further tested in a kinetic radioligand binding competition assay using [ 125 I]ACTH(1‐39) to determine its binding rate constants. CRN04894 rate constants are comparable to published values for other GPCR ligands with k on = 1.2 e 7 M ‐1 min ‐1 and k off = 0.018 min ‐1 , corresponding to a dissociation t 1/2 of 39 min. The kinetic K i (1.5 nM) calculated from the k on and k off is in accordance with the equilibrium competition binding K i and Schild analysis K B . In addition, CRN04894 selectively blocks the ACTH‐MC2R interaction, showing no binding to MC1R, MC3R, MC4R, and MC5R at concentrations ≥ 1 µM. To our knowledge, this class of molecule represents the first reported potent nonpeptide MC2R antagonists, and CRN04894 is currently being evaluated in a first‐in‐human phase 1 clinical trial evaluating pharmacokinetics, pharmacodynamics, and tolerability in healthy subjects.