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: 9792246
• 负责人: Fanny Astruc Diaz
• 金额: $ 93.73万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9792246
• 关键词: Address; Adverse effects; Azoles; CYP26B1 gene; Chemicals; Chronic; Clinical; Collaborations; Congenital ichthyosis; Cytochrome P450; Cytochromes; Data; Dermatitis; Development Plans; Disease; Dose; Drug Kinetics; Dryness; Electrical Resistance; Enzymes; Epidermis; Epithelial; Event; Excipients; Exhibits; Failure; Family; Family member; Formulation; Gene Expression; Genetic Diseases; Goals; Heme; Hereditary Disease; Human; Hyperkeratosis; Keratosis Follicularis; Lead; Liarozole; Liver Microsomes; Measures; Mediating; Medicine; Metabolic; Metabolism; Microsomes; Modeling; Mus; Nonbullous congenital ichthyosiform erythroderma; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiological; Protein Isoforms; Pruritus; Quality of life; Receptor Activation; Retinoic Acid Receptor; Retinoids; Rodent; Role; Safety; Signs and Symptoms; Skin; Small Business Innovation Research Grant; Structure; Therapeutic; Therapeutic Agents; Thinness; Tissues; Topical application; Toxic effect; Toxicogenetics; Toxicology; Tretinoin; Universities; X-Linked Ichthyosis; base; clinical candidate; compliance behavior; cytotoxicity; design; disorders of keratinization; drug candidate; genotoxicity; improved; in vivo; inhibitor/antagonist; irritation; keratinocyte; keratinocyte differentiation; lead optimization; meetings; nanomolar; neglect; next generation sequencing; novel; phase 1 study; pre-clinical; preclinical development; preclinical safety; preclinical toxicity; protein expression; psychosocial; public health relevance; retinoic acid 4-hydroxylase; risk minimization; safety study; scaffold; scale up; side effect; therapeutic target

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.

项目总结/摘要 DermaXon的项目目标是开发有效的基于底物的高选择性CYP26抑制剂， 负责表皮中视黄酸（RA）代谢的酶，用于鱼鳞病的局部治疗。 这种方法将提供一个治疗鱼鳞病的优势，没有潜在的不良反应介导的 通过非靶向P450抑制，与先前描述的非特异性含唑CYP 26相关 抑制剂，如利阿唑。先天性鱼鳞病是一个家族的遗传性疾病的角化 其特征在于干燥、脱皮的皮肤，可能变厚或非常薄，影响患者的生活质量， 他们的家人。目前，没有治愈鱼鳞病和可用的药物是针对只有在 保湿和去角质，减少皮肤干燥，脱皮和开裂。已知RA衍生物 使角质形成细胞的异常分化正常化，并具有减轻角化过度的角质溶解作用， 鱼鳞病患者。然而，RA在人体内的药代动力学较差，因为它诱导其自身的 由于粘膜皮肤副作用， 和刺激。RA在皮肤中的清除主要由细胞色素P450家族26亚型介导 CYP26A1和CYP26B1。目前批准的局部RAR β/γ-选择性类维生素A，其作用由 直接受体激活，也是CYP26A1和B1的强效抑制剂，这可能解释了它们的不良反应。 副作用包括类维生素A皮炎和由类维生素A超负荷引起。在第一阶段的初步研究中，我们 已经确定了一种有效和选择性的CYP26A1和B1双重抑制剂，具有良好的安全性， 在隐性X连锁板层状鱼鳞病中增强生理剂量RA的效果的良好功效 鱼鳞病和Darier病衍生的重建人类表皮。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，其功效是 患者来源的重建人类表皮，这将是准备临床前的发展，如果我们确定 临床前候选药物在早期毒理学研究中失败，2）将我们的双重CYP 26抑制剂从优化的 将分子导向适合于临床前毒性研究临床前候选物，和3）最终启动临床前 开发研究，以证明我们的药物级临床前候选药物的安全性。年底前 在这个项目中，DermaXon将确定一种强效、选择性、局部活性、安全有效的CYP 26 可治疗鱼鳞病临床前皮肤模型中角化病症的抑制剂，其具有增强 内源性RA在体内的作用，并准备进行IND使能的正式关键体内研究，以解决 表皮分化障碍的治疗需求。