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

项目摘要/摘要 DermaXon的项目目标是开发基于底物的高效和高选择性的CYP26抑制剂， 负责表皮中维甲酸(RA)代谢的酶，用于局部治疗鱼鳞病。 这种方法将为鱼鳞病提供治疗优势，而不会产生潜在的不良反应。 通过非靶向P450抑制，与先前描述的非特异性含唑的CYP26相关 抑制剂，如利阿罗唑。先天性鱼鳞病是一种遗传性角化性疾病 以干燥、鳞屑为特征的皮肤可能变厚或非常薄，影响患者的生活质量和 他们的家人。目前，鱼鳞病还没有治愈的方法，现有的药物只针对 保湿去角质，减少皮肤干燥、结垢和龟裂。已知RA衍生品 使角质形成细胞的异常分化正常化，并具有缓解角化过度的角化作用 鱼鳞病患者。然而，RA在人体内的药代动力学很差，因为它会诱导自己 由于粘膜皮肤副作用，上调代谢酶的清除及其局部使用受到限制 和恼怒。RA在皮肤中的清除主要由细胞色素P450家族26亚型介导 细胞色素P26A1和细胞色素P26B1。目前批准的局部RARβ/γ选择性维甲酸，其作用是通过 直接受体激活，也是CYP26A1和B1的有效抑制物，这可能解释了它们的不利 副作用包括维甲酸皮炎，并由维甲酸超载引起。在第一阶段的初步研究中，我们 已经确定了一种有效的和选择性的CYP26A1和B1的双重抑制剂，具有良好的安全性，并且 增强生理剂量维甲酸对隐性X连锁板层状鱼鳞病的疗效 由鱼鳞病和达里尔氏病衍生出来的重建人类表皮。第二阶段的主要里程碑 项目是，1)确定一种来自不同化学支架的备用化合物，在 患者来源的重建人类表皮，如果我们发现，它将为临床前开发做好准备 临床前候选药物在早期毒理学研究中失败，2)将我们的双CYP26抑制剂从优化的 引导分子进入临床前候选，用于临床前毒性研究；3)最终启动临床前 开发研究，以证明我们的药剂级临床前候选药物的安全性。到年底的时候 这项名为DermaXon的项目将确定一种有效的、选择性的、局部活性的、安全有效的CyP26 一种可治疗临床前鱼鳞病皮肤模型角化障碍的抑制剂，具有增强疗效 内源性RA在体内的作用，并准备好进行正式的体内关键研究，以解决 表皮分化障碍的治疗需求。

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.