Selective Cyp26 Antagonists

About

Retinoid agonists, such as acitretin (Soriatane), have been successfully used for dermatological indications including dermatitis and psoriasis due to retinoic acid dysregulation. In the case of psoriasis retinoid treatment inhibits keratinocyte proliferation and differentiation. However, their use is limited as they are teratogens and several serious side effects have been linked to their use including hypertriglyceridemia, fatty liver, and in rare instances, depression and suicidal tendencies. Such side effects led to Roche removing their lucrative anti-acne drug, Accutane, from market. Another major issue for retinoids is that they stimulate expression of Cyp26 proteins and induce their own metabolism. This can occur to such an extent to cause RA drug resistance. The approach of this start-up, 26Therapeutics, is to block the catabolism of endogenous retinoic acid in the dermis and epidermis through application of topical selective inhibitor of Cyp26 isoforms. This approach will result in the accumulation of endogenously produced retinoic acid in the skin layers while significantly reducing systemic RA build up, thereby significantly reducing or eliminating potential side effects observed in some cases of systemic retinoid therapy. Endogenously, RA is metabolized by the Cyp26 family of enzymes. The Cyp26 family of enzymes includes isoforms Cyp26A1, Cyp26B1 and Cyp26C1. All three were discovered in the laboratory of Queen’s University researchers. Cyp26 inhibitor compounds, such as talarazole and liarazole, have been used with clinical success in treating dermatological diseases including psoriasis. However, they lack selectivity for Cyp26 isoforms and, due to their azole‑based chemical structure, they are promiscuous for other P450 enzymes. This is due to the azole structure interfering with heme which is at the catalytic core of all cytochrome P450s. Thus, although the azole based compounds illustrate the great potential of targeting the degradation of local RA, they also inherently carry the risk of disrupting other important cytochrome P450-dependent metabolic processes. These inhibitors do not target heme, but rather, target the substrate binding pocket and are therefore exhibit greater selectivity compared to the azole based inhibitors. Through genetic experiments, these enzymes have been validated as viable therapeutic targets for the treatment of skin disorders. Prior Cyp26 inhibitors such as liarozole and talarozole have lacked potency and selectivity for the individual Cyp enzymes. Queen’s researchers have discovered novel small molecules with high selectivity for the individual Cyp26 isoforms – in particular Cyp26 A1 and B1. In particular these Cyp26A1 inhibitors should have significant benefits in treating atopic dermatitis (AD) and psoriasis. For example it is known that skin of AD is low in retinoic acid likely due to overexpression of Cyp26A1. As an initial proof-of-concept for dermatological uses, the researchers have tested these compounds in the Hairless (rhino) mutant mouse (Hrrh/rh) – a model of human acne. The rhino phenotype is due to an autosomal recessive mutation in the hairless (hr) gene and has been useful in assessing the comedolytic activity of compounds. The skin of these mice develop hard keratinized utriculi, similar to human acne. This model has also been used to assess activity of retinoids in vivo, which reduce size of utriculi. Using this model a two week topical application of TST-026 alone on rhino mouse skin, dramatically reduces utriculi and promotes epidermal thickening indicating therapeutic potential for treating human acne. Retinoic acid ultimately activates gene expression via retinoic acid response elements (RARE). The researchers tracked RARE activation using a RARE-LacZ transgene and found strong RA-induced activation of RARE-LacZ transgene in epidermal keratinocytes from application of TST-26. In all these data support the action of these compounds in vivo and that they can locally increase retinoic acid activity in the skin to treat various dermatological diseases.