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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 DermaXon 的项目目标是开发用于局部治疗的有效新型选择性 CYP26A1 抑制剂先天性鱼鳞病是一种遗传性角化病，其特征是干燥、鳞屑皮肤可能增厚或非常薄，影响患者及其家人的生活质量。目前，鱼鳞病尚无治愈方法，现有药物仅针对保湿和去角质减少皮肤干燥、脱屑和龟裂已知视黄酸 (RA) 衍生物可以使异常现象正常化。角质形成细胞的分化，并具有角质层分离作用，可减轻角化过度的患者然而，RA 在人体中的药代动力学较差，因为它通过诱导自身清除。上调代谢酶及其使用由于皮肤粘膜副作用、代谢异常而受到限制血清脂质谱、骨刺和脱发 RA 的清除主要由细胞色素介导。 P450家族有26种酶（CYP26）其中有3种亚型：CYP26A1、CYP26B1和CYP26C1。 DermaXon 首次证明 CYP26A1 是负责人体皮肤 RA 代谢的亚型。目前批准的局部RARβ/γ-选择性维A酸，其作用是通过直接受体激活介导的，也是 CYP26A1 和 B1 的有效非选择性抑制剂，这可能解释了它们的不良副作用包括类视黄醇皮炎在本 STTR 中，DermaXon 将证明选择性抑制 CYP26A1 将有效。增加鱼鳞病皮肤中的 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。我们是唯一一组没有与其他 CYP26 的非特异性抑制相关的副作用的鱼鳞病。在全球范围内开发出选择性纳摩尔 CYP26A1 抑制剂，提供新的治疗类别这些抑制剂对 CYP26A1 具有高度选择性，可避免引起的不良反应。通过与先前描述的非特异性含唑 CYP26 相关的非靶向 P450 抑制我们非常适合证明 CYP26A1 作为治疗靶点的效用。因为我们汇集了 DermaXon（药物专家）之间学术与工业合作伙伴关系的专业知识发现和制定）和西北大学（Paller 博士，鱼鳞病专家）在此提议的奖项中。在此期间，DermaXon 将完成先前开发的先导候选结构的表征，该结构是高效且选择性的 CYP26A1 抑制剂将评估这些 CYP26A1 抑制剂的作用。并与双重 CYP26A1/B1 抑制剂和选择性 CYP26B1 抑制剂对增加 RA 的作用进行比较从鱼鳞病患者分离的角质形成细胞中以及在人表皮模型中的浓度到该项目结束时，DermaXon 将鉴定出一种有效、选择性、局部活性、安全且有效的药物。有效的 CYP26 抑制剂，可治疗鱼鳞病临床前皮肤模型中的角化障碍，为支持 IND 的正式研究做好准备，以满足鱼鳞病的治疗需求。