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

项目摘要/摘要 DermaXon的项目目标是开发用于局部治疗的有效的新型CYP26A1选择性抑制剂 患上了鱼鳞病。先天性鱼鳞病是一种遗传性角化性疾病家族，其特征是干燥， 结垢的皮肤可能变厚或非常薄，影响患者及其家人的生活质量。 目前，鱼鳞病还没有治愈方法，现有的药物只针对保湿和去角质。 减少皮肤干燥、结垢和龟裂。已知维甲酸(RA)衍生物可使异常情况正常化 角质形成细胞的分化，并具有角化溶解作用，减轻角化过度的患者 鱼鳞病。然而，RA在人体内的药代动力学很差，因为它通过以下途径诱导自身清除 上调代谢酶及其使用由于粘膜皮肤副作用，异常的皮肤 血脂、骨刺和脱发。RA的清除主要是由细胞色素介导的 P450家族26种酶(CYP26)，其中有三种亚型：CYP26A1、CYP26B1和CYP26C1。为 第一次，DermaXon证明了CYP26A1是负责人体皮肤中RA新陈代谢的异构体。 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介导的， 也是CYP26A1和B1的有效的非选择性抑制剂，这可能解释了它们的不良副作用 包括维甲酸皮炎。在这篇STTR中，DermaXon将证明选择性抑制CYP26A1将 增加鱼鳞病皮肤中RA浓度，导致角质形成细胞分化正常化和 减轻与鱼鳞病相关的角化过度。这种方法将在以下方面提供治疗优势 鱼鳞病，无与其他CYP26的非特异性抑制相关的副作用。我们是唯一一个 全球已开发出选择性纳米分子CYP26A1抑制剂，提供了一种新的治疗类别 治疗鱼鳞病。这些抑制剂对CYP26A1具有高度的选择性，避免了引起的不良反应 通过与先前描述的非特异性含唑细胞色素P450 26相关的非靶向P450抑制 抑制剂，如利阿罗唑。我们是唯一适合证明细胞色素P26A1作为治疗靶点的实用性 由于我们汇集了DermaXon(药物专家)之间学术和行业合作伙伴关系的专业知识 )和西北大学(Paller博士，鱼鳞病专家)。在这项拟议的奖项中 期间，DermaXon将完成对先前开发的领先候选结构的表征，这些结构 是高度有效和选择性的CYP26A1抑制剂。这些CYP26A1抑制剂的效果将被评估 并比较了双重CYP26A1/B1抑制剂和选择性CYP26B1抑制剂在增加RA方面的作用 从鱼鳞病患者分离的角质形成细胞中的浓度，以及在人的表皮模型中的浓度 鱼鳞病。到这个项目结束时，DermaXon将确定一种有效的、选择性的、局部活性的、安全的和 有效的CYP26抑制剂，可以治疗临床前鱼鳞病皮肤模型中的角化障碍， 为IND做好准备-使正式研究能够解决鱼鳞病的治疗需求。

Project Summary / Abstract DermaXon’s project goal is to develop efficacious novel selective inhibitors of CYP26A1 for the topical treatment of ichthyosis. 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. Retinoic acid (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 use is limited due to mucocutaneous side-effects, abnormalities of serum lipid profiles, bone spurs and hair loss. The clearance of RA is predominantly mediated by cytochrome P450 family 26 enzymes (CYP26) of which there are three isoforms: CYP26A1, CYP26B1 and CYP26C1. For the first time, DermaXon has shown that CYP26A1 is the isoform responsible for RA metabolism in human skin. Currently approved topical RARβ/γ-selective retinoids, whose effects are mediated by direct receptors activation, are also potent non-selective inhibitors of both CYP26A1 and B1, which likely explains their adverse side effects including retinoid dermatitis. In this STTR, DermaXon will demonstrate that selective inhibition of CYP26A1 will increase RA concentration in ichthyotic skin, resulting in normalization of keratinocyte differentiation and mitigating hyperkeratosis associated with ichthyosis. This approach will provide a therapeutic advantage in ichthyosis without side effects associated with non-specific inhibition of other CYP26s. We are the only group world-wide to have developed selective nanomolar CYP26A1 inhibitors, providing a new therapeutic class against ichthyosis. These inhibitors shown to be highly selective for CYP26A1, avoid the adverse effects induced by non-targeted P450 inhibition associated with previously described non-specific azole-containing CYP26 inhibitors, such as liarozole. We are uniquely suited to demonstrate the utility of CYP26A1 as a therapeutic target as we bring together the expertise of academic-industry partnerships between DermaXon (expert in drug discovery and formulation) and Northwestern University (Dr. Paller, expert in ichthyosis). In this proposed award period, DermaXon will complete the characterization of the previously developed lead candidate structures which are highly potent and selective CYP26A1 inhibitors. The effects of these CYP26A1 inhibitors will be assessed and compared to the effects of a dual CYP26A1/B1 inhibitor and a selective CYP26B1 inhibitor at increasing RA concentration in keratinocytes isolated from patients with ichthyosis, and in a human epidermis model of ichthyosis. 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 and, ready for IND-enabling formal studies to address the therapeutic needs in ichthyosis.