Project Summary / Abstract
DermaXon's project goal is to develop efficacious, substrate-based, selective inhibitors of CYP26s, the enzymes
responsible for the metabolism of all-trans retinoic acid (atRA) in the epidermis, as an oral treatment for severe
recalcitrant acne. This approach will provide an improved acne therapeutic without the adverse effects
associated with currently marketed retinoids. This would also avoid the potential adverse effects caused by the
off-target cytochrome P450 (CYP) inhibition seen with previously investigated azole-containing CYP26 inhibitors
such as liarozole. Acne affects more than 40 million Americans, costs upwards of $3 billion annually, and has a
significant negative impact on quality of life. Acne patients have been shown to experience levels of social,
psychological and emotional distress similar to those reported in epileptic and diabetic patients. Retinoids, a
class of atRA-related compounds, possess comedolytic and anti-inflammatory properties. However,
considerable adverse effects including erythema, pruritus, dryness, and peeling, as well as systemic adverse
effects on mucocutaneous, musculoskeletal, and ophthalmic systems, are limiting factors. Clearance of atRA in
the skin is predominantly mediated by the CYP family 26 isoforms CYP26A1 and CYP26B1. Currently approved
topical retinoids targeting direct activation of retinoic acid receptors, are also potent inhibitors of both CYP26A1
and B1, which likely explains their adverse side effects related to retinoid pathway overstimulation. We have
potent and selective inhibitors of CYP26A1 and/or B1. Our preliminary data demonstrates that these inhibitors:
a) are specific CYP26 inhibitor which do not interact with nuclear receptors and off-target CYPs, b) potentiates
the effects of a nanomolar concentration of atRA in reconstructed human epidermis, c) are not genotoxic,
cardiotoxic, or irritant, d) exhibits comedolytic efficacy in vivo e) are orally bioavailable and f) are manufacturable.
The studies in Aim 1 focus on completing the oral characterization of these compounds and their biodistribution
in skin and plasma in vivo. The studies in Aim 2 will focus on the oral dose range efficacy studies in rhino mice.
In Aim 3, we will determine the embryo-fetal development toxicity of the selected inhibitor at the active dose. By
the end of this project, DermaXon will have identified an oral CYP26 ready for IND-enabling studies addressing
the therapeutic needs of severe acne patients.
