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

项目总结/摘要 DermaXon的项目目标是开发有效的新型CYP 26 A1选择性抑制剂，用于局部治疗 鱼鳞病先天性鱼鳞病是一个家族的遗传性角质化疾病的特点是干燥， 刮除可能增厚或非常薄的皮肤，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，可用的药物仅针对保湿和去角质 减少皮肤干燥、脱皮和开裂。已知视黄酸（RA）衍生物使异常的 角化细胞的分化，并具有缓解患有角化过度的患者中的角化过度的角化作用。 鱼鳞病。然而，RA在人体中的药代动力学较差，因为它通过以下途径诱导自身清除： 上调代谢酶，并且由于粘膜皮肤副作用、 血脂、骨刺和脱发。RA的清除主要由细胞色素介导 P450家族26种酶（CYP 26），其中有三种亚型：CYP 26 A1、CYP 26 B1和CYP 26 C1。为 DermaXon首次证明CYP 26 A1是人体皮肤中负责RA代谢的同种型。 目前批准的局部RARβ/γ-选择性类维生素A，其作用由直接受体激活介导， 也是CYP 26 A1和B1的强效非选择性抑制剂，这可能解释了它们的不良副作用 包括维甲酸皮炎。在本STTR中，DermaXon将证明选择性抑制CYP 26 A1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， 减轻与鱼鳞病相关的角化过度。这种方法将提供治疗优势， 鱼鳞病，无其他CYP 26非特异性抑制相关副作用。我们是唯一一个 世界范围内已经开发出选择性纳摩尔CYP 26 A1抑制剂，提供了一种新的治疗类别 对抗鱼鳞病这些抑制剂显示对CYP 26 A1具有高度选择性，避免了诱导的不良反应 通过与先前描述的非特异性含唑CYP 26相关的非靶向P450抑制 抑制剂，如利阿唑。我们是唯一适合证明CYP 26 A1作为治疗靶点的效用 我们将DermaXon（药物领域的专家） 发现和配方）和西北大学（Paller博士，鱼鳞病专家）。在这份裁决书中， 在此期间，DermaXon将完成先前开发的主要候选结构的表征， 是高效和选择性的CYP 26 A1抑制剂。将评估这些CYP 26 A1抑制剂的作用 并与双重CYP 26 A1/B1抑制剂和选择性CYP 26 B1抑制剂对增加RA的作用进行比较 在从患有鱼鳞病的患者分离的角质形成细胞中，以及在患有鱼鳞病的人表皮模型中， 鱼鳞病。到本项目结束时，DermaXon将确定一种有效的，选择性的，局部活性的，安全的， 有效CYP 26抑制剂可治疗鱼鳞病的临床前皮肤模型中的角化病症， 为IND启动正式研究做好准备，以满足鱼鳞病的治疗需求。

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.