Endogenous
Cushing's syndrome (CS) is a set of disorders caused by chronic exposure to excess
glucocorticoids induced by
neuroendocrine tumors in pituitary, adrenals, and infrequently other sites (
ectopic ACTH syndrome). Due to various comorbidities, CS patients exhibit higher risks of
cardiovascular diseases and thus increased mortality.
Pharmaceutical therapy is an important constituent of treatment regimen. Areas covered: Patents published since 2012 are reviewed, which claim therapeutic compounds interfering with
ACTH secretion and down-stream signal transduction, inhibiting
cortisol biosynthesis and antagonizing
glucocorticoid receptors. Advances focus on a) new analogues with improved efficacy and PK properties or less off-target toxicity; b) existing drugs (candidates) being repurposed to treat CS; and c) novel strategies such as selective inhibition of
CYP11B1. Expert opinion: New compounds against established targets need to be developed because current drugs lack selectivity leading to off-target toxicity. Selective inhibition of
CYP11B1 is a novel alternative strategy and is potentially versatile in controlling all types of
hypercortisolism. Selective multi-targeting
enzymes in steroidogenesis network is promising due to potential synergistic effects. However, doses toward each targets are not feasible to adjust because the corresponding intrinsic potencies are rigid. Targeting PRKACA mutations is promising in treating CS caused by adrenal
adenomas.