Selective inhibition of CYP26A1 in the skin for the treatment of ichthyosis

项目摘要/摘要

Project Summary / Abstract DermaXon’s project goal is to develop efficacious substrate-based and highly selective inhibitors of CYP26s, the enzymes responsible or retinoic acid (RA) metabolism in the epidermis, for the topical treatment of ichthyosis. This approach will provide a therapeutic advantage in ichthyosis without the potential adverse effects mediated by non-targeted P450 inhibition, associated with previously described non-specific azole-containing CYP26 inhibitors, such as liarozole. Congenital ichthyosis is a family of hereditary disorders of keratinization characterized by dry, scaling skin that may be thickened or very thin, impacting the quality of life of patients and their family members. Currently, there is no cure for ichthyosis and available medicines are aimed only at moisturizing and exfoliating to reduce dryness, scaling and cracking of skin. RA derivatives are known to normalize abnormal differentiation of keratinocytes and have keratolytic effects that mitigate hyperkeratosis in patients with ichthyosis. However, RA has poor pharmacokinetics in humans because it induces its own clearance by upregulating metabolic enzymes and its topical use is limited due to mucocutaneous side-effects and irritation. The clearance of RA in the skin is predominantly mediated by cytochrome P450 family 26 isoforms CYP26A1 and CYP26B1. Currently approved topical RARβ/γ-selective retinoids, whose effects are mediated by direct receptors activation, are also potent inhibitors of both CYP26A1 and B1, which likely explains their adverse side effects including retinoid dermatitis, and induced by retinoid overload. In a preliminary Phase I study, we have identified a potent and selective dual inhibitor of CYP26A1 and B1 with a promising safety profile, and a good efficacy at potentiating the effect of a physiological dose of RA in lamellar ichthyosis, recessive X-linked ichthyosis and Darier’s disease derived reconstruct human epidermis. The major milestones in this Phase II project are, 1) to identify a backup compound originating from a different chemical scaffold, with efficacy in patient-derived reconstruct human epidermis, which will be ready for preclinical development if our identified preclinical candidate fails in early toxicological studies, 2) to advance our dual CYP26 inhibitor from optimized lead molecule to preclinical candidate suitable, for preclinical toxicity studies and, 3) finally to initiate preclinical development studies to demonstrate the safety of our pharmaceutical grade preclinical candidate. By the end of this project, DermaXon will have identified a potent, selective, topically active, safe and efficacious CYP26 inhibitor that can treat keratinization disorders in preclinical skin models of ichthyosis, with efficacy at potentiating the effect of endogenous RA in vivo, and ready for IND-enabling formal pivotal in vivo studies to address the therapeutic needs in disorders of epidermal differentiation.