The potential of targeting CYP11B

ABSTRACT

Introduction: Members of the CYP11B subfamily participate in the biosynthesis of important steroid hormones. CYP11B1 catalyzes the formation of cortisol, while CYP11B2 realizes the biosynthesis of aldosterone. Overproduction of cortisol is related to Cushing’s disease, whereas overproduction of aldosterone leads to hypertension and end-organ damage such as cardiac and renal hypertrophy. Therefore, CYP11B1 and CYP11B2 have been defined as interesting targets for the development of novel drugs.

Areas covered: The paper describes the CYP11B1 and CYP11B2 genes and proteins, giving special attention to their functional and structural properties, the development of efficient test systems for potential inhibitors of both CYPs and the development and testing of novel potential drugs on the basis of selective inhibition of CYP11B1 and CYP11B2.

Expert opinion: The availability of relevant and efficient screening systems for testing the effects of inhibitors of human CYP11B1 and CYP11B2, combined with experiences and success in synthesizing selective and efficient inhibitors of these isoenzymes, provides a realistic basis for a successful development of drugs using CYP11B1 and CYP11B2 as targets. The first clinical trials with the CYP11B2 inhibitor LCI699 demonstrated some side effects but showed inhibition of end-organ damage in animals, indicating that it might be a useful lead compound for future developments.

KEYWORDS:

• Adrenodoxin
• adrenodoxin reductase
• aldosterone
• aldosteronism
• cortisol
• corticosterone
• Cushing’s disease
• cytochrome P450
• CYP11B1
• CYP11B2
• LCI699
• NADPH-cytochrome P450 reductase

Article highlights

• The structure and function of CYP11B1 and CYP11B2 genes and proteins is described.

• Consequences of overproduction of cortisol by CYP11B1 and aldosterone by CYP11B2 are demonstrated.

• The development of test systems for the evaluation of selective and specific inhibitors of both proteins is described.

• Recent developments concerning the synthesis and application of inhibitors of CYP11B1 and CYP11B2 are discussed, with special attention to LCI699 which was tested in clinical trials.

• Suggestions for further improvement of CYP11B1 and CYP11B2 inhibitors for application as drugs are given.

This box summarizes key points contained in the article.

Acknowledgments

The author thanks Lina Schiffer, Martin Litzenburger and Antje Eiden-Plach for help with the Figures and References. Critical reading of the manuscript by Frank Hannemann, Jens Neunzig and Lina Schiffer is greatly acknowledged.

Financial and competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.