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

选择性抑制皮肤CYP26A1治疗鱼鳞病

• 批准号: 9255097
• 负责人: Fanny Astruc Diaz
• 金额: $ 21.56万
• 依托单位: DERMAXON, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9255097
• 关键词: Address; Adverse effects; Affect; Award; Azoles; Birth; Bone Spur; CYP26B1 gene; Chronic; Clinical; Clinical Research; Congenital ichthyosis; Cytochrome P450; Cytochromes; Data; Dermatitis; Disease; Dose; Drug Formulations; Drug Kinetics; Dryness; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epidermis; Family; Family member; Formulation; Gene Expression; Genes; Goals; Hair; Hepatotoxicity; Hereditary Disease; Human; Hyperkeratosis; Ichthyoses; In Vitro; Individual; Investigational New Drug Application; Lead; Liarozole; Life; Lipids; Mediating; Medicine; Metabolic; Metabolism; Modeling; Molecular Biology; Pain; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Protein Isoforms; Pruritus; Quality of life; Receptor Activation; Retinoids; Role; Series; Serum; Signs and Symptoms; Skin; Small Business Technology Transfer Research; Structure; Testing; Therapeutic; Therapeutic Agents; Time; Tretinoin; United States; Universities; abstracting; clinical efficacy; compliance behavior; drug discovery; improved; industry partner; inhibitor/antagonist; keratinization; keratinocyte; keratinocyte differentiation; nanomolar; neglect; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; psychosocial; public health relevance; retinoic acid 4-hydroxylase; therapeutic target

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.

项目摘要 /摘要 Dermaxon的项目目标是为局部处理开发有效的CYP26A1的新型选择性抑制剂 鱼质病。先天性鱼质病是一个以干性为特征的角质性遗传性疾病的家族 缩放皮肤可能会变稠或非常薄，从而影响患者及其家人的生活质量。 目前，尚无治愈鱼类病的方法，可用的药物仅针对保湿和去角质 为了减少干燥，皮肤缩放和开裂。视黄酸（RA）衍生物已知将异常归一化 角质形成细胞的分化并具有角化液作用，可减轻 鱼性病。但是，RA在人类中的药代动力学差，因为它通过 上调代谢酶及其使用受到粘膜副作用，异常的限制 血清脂质谱，骨马刺和脱发。 RA的清除主要由细胞色素介导 P450家族26酶（CYP26），其中有三种同工型：CYP26A1，CYP26B1和CYP26C1。为了 Dermaxon首次表明CYP26A1是负责人皮肤中RA代谢的同工型。 当前批准的局部RARβ/γ选择性类维生素类似于其作用是由直接受体激活介导的 也是CYP26A1和B1的潜在非选择性抑制剂，这可能解释了它们的不良副作用 包括类维生素性皮炎。在此Sttr中，Dermaxon将证明CYP26A1的选择性抑制作用将 增加了鱼酸皮肤的RA浓度，从而导致角质形成细胞分化的标准化和 缓解与鱼质病相关的高胚症。这种方法将在 没有副作用的鱼质病与其他CYP26的非特异性抑制有关。我们是唯一的团体 在全球范围内开发了选择性纳摩尔CYP26A1抑制剂，提供了新的治疗类别 反对鱼质病。这些抑制剂证明对CYP26A1具有高度选择性，避免引起的不良反应 通过与先前描述的非特异性Azole CYP26相关的非靶向P450抑制作用 抑制剂，例如叶绿素。我们非常适合证明CYP26A1作为治疗靶标的实用性 当我们将Dermaxon（药物专家）之间的学术行业合作伙伴关系汇集在一起​​时 发现与配方）和西北大学（帕勒博士，鱼虫病专家）。在这个拟议的奖项中 时期，Dermaxon将完成先前开发的主要候选结构的表征 是高潜力和选择性CYP26A1抑制剂。将评估这些CYP26A1抑制剂的影响 并将双重CYP26A1/B1抑制剂和选择性CYP26B1抑制剂的影响与RA的增加相比 从鱼性病患者和人类表皮模型中分离出的角质形成细胞的浓度 鱼性病。到该项目结束时，Dermaxon将确定潜力，选择性，局部活跃，安全和 有效的CYP26抑制剂可以治疗临床前皮肤模型的角化疾病，并 准备好进行正式研究，以满足鱼质病的治疗需求。