A series of compounds was synthesized using rational drug-based design. These compounds represent significant improvements over other clinically tested CYP26 antagonists.

About

Background

Vitamin A metabolism gives rise to several active forms of retinoic acid (RA). Retinoids regulate several physiological functions in multiple organs including the liver, kidney, skin and heart and they play an essential role in immune regulation, cell growth, differentiation, and apoptosis. Retinoids have been used successfully for the treatment of several types of cancer and dermatological indications. However, their use is limited as they are associated with serious side effects and resistance to treatment due induction of RA metabolism via upregulation of CYP26 isoforms. Systemic administration of retinoids is associated with liver toxicity and abnormal serum lipid profiles while topical applications can lead to retinoid dermatitis. Oral retinoid therapy is known to have a teratogenic effect, causing retinoic acid embryopathy which leads to abnormalities of the central nervous system and heart. Roche pulled its blockbuster drug Accutane from the US market due to serious retinoid associated side effects. A new approach to this problem is potentiating endogenous RA. RA metabolism antagonists that inhibit catabolism of endogenous RA, can have therapeutic effect by increasing local RA accumulation in tissues while showing fewer side effects associated with exogenous RA.

Technology Overview

The CYP26 family includes three enzymes CYP26A1, CYP26B1 and CYP26C1. All three were discovered in the laboratory of Queen’s University. CYP26 enzymes metabolize RA limiting RA activity. Queen’s researchers have created and identified novel retinoid-based CYP26A1 inhibitors to target diseases where CYP26A1 overexpression limits or prevents the beneficial activity of endogenous RA.

A series of compounds was synthesized using rational drug-based design and tested for activity against CYP26A1 or CYP26B1 in cell-based systems. The ability of these inhibitors to increase RA and its activity was determined using RA-sensitive luciferase assays and RA-mediated gene expression, both in vitro and in vivo. Highly CYP26A1-selective compounds were identified (> 10,000 fold selectivity over CYP26B1) with high potency (low and sub-nanomolar IC50s). These compounds represent significant improvements over other clinically tested CYP26 antagonists, such as talarazole and liarazole) which lacked the selectivity and potency of these novel CYP26A1 inhibitors. Select compounds and their activities can be seen in Figure 1.

In vivo proof-of-concept for GGP12 efficacy was tested in the hairless (rhino) mutant mice, a mouse model of acne. Topical treatment of GGP12 induced RARE-LacZ activation and significantly reduced the size of utriculi (similar to human acne) suggesting a potential use in the treatment of human acne and other dermatological conditions. Selectivity for the CYP26A1 isoform limits disruption of other metabolic and biosynthetic processes of the cytochrome P450 family.

Key Benefits

Much higher selectivity and potency than existing CYP26 inhibitor compounds.

Lack agonist activity for Retinoic Acid Receptor.

Demonstrated ability to increase local concentration of endogenous RA for treatment efficacy while removing potential retinoid-associated side effects from exogenous RA or retinoid therapy.

High selectivity for Cyp26A1 will reduce any toxicity associated with Pan-CYP26 inhibitors.

Applications

Cyp26A1 is an important drug target for a number of diseases including cancers (pancreatic, cervical, head and neck, renal carcinoma, plus others), liver disease, and heart failure.

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