Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design

Abstract

Primary aldosteronism, the major form of secondary hypertension, develops due to excess steroid hormone aldosterone produced by aldosterone synthase, also known as cytochrome P450 11B2. CYP11B2 is 93% identical to cortisol-producing CYP11B1, which makes it difficult to design selective drugs. LCI699 (Osilodrostat, Isturisa) was initially developed as a CYP11B2 inhibitor but due to poor selectivity was recently repurposed as the first Food and Drug Administration-approved drug for CYP11B1-mediated Cushing disease. Thus, there is still no effective therapeutic option targeting CYP11B2 for primary aldosteronism. Using a structure/function approach, aspects of LCI699 interaction with CYP11B2 were examined to facilitate the design of more selective inhibitors. LCI699 effectively binds and inhibits CYP11B2. To determine the structural basis for this interaction, X-ray crystallography was used to solve the structure of CYP11B2 bound to LCI699. LCI699 binds in the active site with its imidazole nitrogen coordinating the heme iron. LCI699 binding was compared with that of its analog fadrozole to both CYP11B enzymes. Comparison with the CYP11B1 structure reveals distinct CYP11B active site architectures which can be exploited to directed drug design. Exploiting structural differences between the CYP11B enzymes will promote the design of therapeutics for the treatment of primary aldosteronism targeting CYP11B2 while reducing undesirable side effects due to off-target CYP11B1 inhibition.