Development of TAK1 Compounds for Neonatal Onset Multisystem Inflammatory Disease

开发治疗新生儿多系统炎症性疾病的 TAK1 化合物

• 批准号: 8828382
• 负责人: Joseph B Monahan
• 金额: $ 22.49万
• 依托单位: CONFLUENCE LIFE SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828382
• 关键词: Anabolism; Attenuated; Autoimmune Process; Basic Science; Biological Assay; Biological Models; Biological Sciences; Blood; Blood Cells; Bone Marrow; California; Chemicals; Chronic; Clinical Research; Clinical Sciences; Clinical Trials; Data; Development; Disease; Disease model; Dose; Drug Design; Drug Formulations; Drug Kinetics; Drug Targeting; Evaluation; Exanthema; Family; Fever; Funding; Genetic Models; Goals; Growth; Human; Impairment; In Vitro; Industry; Inflammation; Inflammatory; Interleukin-1; Interleukin-18; Lead; Lesion; Libraries; Licensing; MAP3K7 gene; MAPK14 gene; Medical; Meningitis; Modeling; Mus; Mutation; Neonatal; Oral; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenocopy; Phenotype; Phosphotransferases; Positioning Attribute; Price; Production; Property; Proteins; Psyche structure; Quality of life; Recurrence; Resistance; Resistance development; Role; Safety; Sampling; Seizures; Signal Transduction; Small Business Innovation Research Grant; Staging; Structure; Symptoms; Syndrome; System; Testing; Therapeutic; Time; Toxicology; Transforming Growth Factors; Universities; anakinra; base; bone mass; cost; deafness; drug candidate; drug development; drug discovery; experience; improved; in vivo; inhibitor/antagonist; innovation; interest; kinase inhibitor; lead series; macrophage; marenostrin; phase 2 study; pre-clinical; product development; programs; public health relevance; receptor; research clinical testing; scale up; skeletal; small molecule; standard care; stress-activated protein kinase 1

DESCRIPTION (provided by applicant): Cryopyrin-associated periodic syndromes (CAPS) are a family of rare autoinflammatory diseases of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID is characterized by NLRP3 activating mutations resulting in excessive interleukin- 1�IL-1�and IL-18 production associated with recurrent fever, rash, skeletal lesions, chronic meningitis, seizures, deafness and mental impairment. Consistent with IL-1� central role in these disorders, protein-based anti-IL-1drugs such as anakinra have demonstrated efficacy in the treatment of NOMID. Unfortunately, these drugs suffer from high price, the requirement for parenteral administration, the potential for development of resistance and the lack of efficacy against skeletal lesions. These shortcomings provide a strong rationale for the development of a safe, more effective and affordable oral inhibitor of IL-1�o treat this disease. IL-1�iosynthesis is regulated by p38 an JNK mitogen-activated protein kinases and I?B kinase and the activation of each is controlled by transforming growth factor-�ctivated kinase 1 (TAK1). TAK1 is critical not only in the biosynthesis of IL-1�IL-18 and NLRP3, but also in IL-1�ignaling, thereby positioning this kinase as a drug target for the treatment of CAPS. In this SBIR Phase I application, Confluence Life Sciences (CLS) proposes to develop the first proprietary TAK1 inhibitor drug candidate for the treatment of CAPS. CLS has developed an innovative kinase drug discovery platform (KINect) that exploits our proprietary kinase inhibitor library in the context of structure-based drug design (SBDD) to rapidly identify and develop active, drug-like chemical cores into drug candidates. Using this approach CLS has recently identified a set of potent and proprietary lead TAK1 inhibitor compounds. From this starting point, CLS proposes to develop TAK1 drug candidates focusing on the following specific aims: (1) Optimize the pharmaceutical properties of two TAK1 inhibitor lead series and determine their efficacy in blocking IL-1�IL-18 and NLRP3 biosynthesis as well as IL-1�ignaling in murine CAPS bone marrow-derived macrophages (BMDM) and peripheral blood mononuclear cells (PBMC) from CAPS patients and (2) Determine the efficacy of TAK1 drug candidates in a murine NOMID model. SBIR phase 2 studies will focus on product development and advancement of the program through human Phase 1 clinical evaluation in CAPS patients. Supporting studies will include regulatory toxicology, pharmacokinetics and drug product synthesis. The resulting product will be of great interest to drug companies and we anticipate a co-development partnership license. Commercial deals for assets at this stage are highly precedented in the industry and typically total >$100M. Given the great need for an effective therapeutic for CAPS, the development of a safe TAK1 inhibitor drug candidate will have a major medical impact.

描述（由申请人提供）：隐热蛋白相关周期性综合征（CAPS）是一类罕见的自身炎症性疾病，其中新生儿发病的多系统炎症性疾病（NOMID）是最严重的表型。 NOMID 的特点是 NLRP3 激活突变，导致白细胞介素 1·IL-1·和 IL-18 产生过多，与反复发烧、皮疹、骨骼病变、慢性脑膜炎、癫痫、耳聋和精神障碍相关。与 IL-1 在这些疾病中的核心作用一致，基于蛋白质的抗 IL-1 药物（如阿那白滞素）已证明在治疗 NOMID 方面有效。不幸的是，这些药物价格昂贵、需要肠外给药、可能产生耐药性以及缺乏针对骨骼病变的功效。这些缺点为开发一种安全、更有效和负担得起的口服 IL-1 抑制剂来治疗这种疾病提供了强有力的理由。 IL-1 的合成受 p38、JNK 丝裂原激活蛋白激酶和 IκB 激酶的调节，并且每种激酶的激活均受转化生长因子激活激酶 1 (TAK1) 控制。 TAK1 不仅在 IL-1·IL-18 和 NLRP3 的生物合成中至关重要，而且在 IL-1·信号传导中也至关重要，因此将该激酶定位为治疗 CAPS 的药物靶点。在本次 SBIR I 期申请中，Confluence Life Sciences (CLS) 提议开发第一个用于治疗 CAPS 的专有 TAK1 抑制剂候选药物。 CLS 开发了一个创新的激酶药物发现平台 (KINect)，该平台在基于结构的药物设计 (SBDD) 背景下利用我们专有的激酶抑制剂库来快速识别活性、类药化学核心并将其开发为候选药物。利用这种方法，CLS 最近确定了一组有效且专有的先导 TAK1 抑制剂化合物。以此为起点，CLS建议开发TAK1候选药物，重点关注以下具体目标：（1）优化两个TAK1抑制剂先导系列的药物特性，并确定它们阻断IL-1·IL-18和NLRP3生物合成以及小鼠CAPS骨髓源性巨噬细胞（BMDM）和外周血单核细胞中IL-1·信号传导的功效 (PBMC) 来自 CAPS 患者，(2) 确定 TAK1 候选药物在小鼠 NOMID 模型中的功效。 SBIR 2 期研究将重点关注通过 CAPS 患者进行的人体 1 期临床评估的产品开发和项目进展。支持研究将包括监管毒理学、药代动力学和药品合成。由此产生的产品将引起制药公司的极大兴趣，我们预计将获得共同开发合作伙伴许可。此阶段的资产商业交易在业内非常有先例，总额通常超过 1 亿美元。鉴于对 CAPS 有效治疗方法的巨大需求，开发安全的 TAK1 抑制剂候选药物将产生重大的医学影响。