Drug design strategies for Cushing’s syndrome

ABSTRACT

Introduction: Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide).

Areas covered: The authors discuss the recent drug developments for the medical treatment of CS through two validated molecular targets. Specifically, the authors look at selective inhibitors of CYP11B1 that reduce cortisol production by inhibiting steroid 11beta-hydroxylase and glucocorticoid receptor (GR) antagonists that interrupt cortisol-mediating transcriptional regulation of related genes.

Expert opinion: Patients with CS have limited treatment options; indeed, there is an unmet need for new compounds that target CYP11B1 selectively versus several steroidogenic enzymes and/or GR-signaling pathways. The complexity of steroid biosynthesis and signaling requires the application of structure-based drug discovery techniques that use molecular targets and highly similar off-targets. Significant differences in steroidogenesis between humans and other species necessitates caution over the choice of in vivo model for the preclinical evaluation of future potential compounds.

KEYWORDS:

• Cushing syndrome
• CYP11B1
• inhibitor
• cytochrome P450
• nuclear receptor
• glucocorticoid receptor
• receptor antagonist

Article highlights

• The currently available medical therapy for treating Cushing’s syndrome does not meet the selectivity criteria for its drug targets versa off-targets resulting in side effects.

• CYP11B1 and the glucocorticoid receptor (GR) are both priority targets in Cushing’s syndrome.

• Nonsteroidal molecules are preferred over steroidal scaffolds.

• CYP11B1 complete inhibition should be avoided, while an appropriate selectivity factor should be achieved over highly homologous CYP11B2.

• The next critical milestone in the discovery of GR antagonists is the crystal structure of the full-length receptor

• Species-specific differences in steroidogenesis should be considered during drug development.

This box summarizes key points contained in the article.

Declaration of interest

A Kliuchenovich is an employee of Target Medicals LLC. The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.