Development of TAK1 Compounds for Neonatal Onset Multisystem Inflammatory Disease

描述（由申请人提供）：Cryopyrin相关周期性综合征（CAPS）是一种罕见的自身炎性疾病家族，其中脑源性多系统炎性疾病（NOMID）是最严重的表型。NOMID的特征是NLRP 3激活突变，导致过量的白细胞介素-1-IL-1-和IL-18产生，与反复发热、皮疹、骨骼病变、慢性脑膜炎、癫痫发作、耳聋和精神损害有关。与IL-1在这些疾病中的中心作用一致，基于蛋白质的抗IL-1药物如阿那白滞素已被证明在治疗NOMID中有效。不幸的是，这些药物具有价格高、需要肠胃外给药、产生耐药性的可能性以及缺乏对抗骨骼病变的功效的缺点。这些缺点为开发安全，更有效和负担得起的IL-1 β口服抑制剂治疗这种疾病提供了强有力的理由。IL-1 β的合成受p38和JNK丝裂原活化蛋白激酶和I？B激酶，每种激酶的激活都受转化生长因子激活激酶1（TAK 1）的控制。TAK 1不仅在IL-1、IL-18和NLRP 3的生物合成中至关重要，而且在IL-1信号转导中也至关重要，因此将这种激酶定位为治疗CAPS的药物靶点。在这项SBIR I期申请中，Confluence Life Sciences（CLS）提议开发第一种用于治疗CAPS的专有TAK 1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）的背景下利用我们专有的激酶抑制剂库，快速识别和开发活性的药物样化学核心成为候选药物。使用这种方法，CLS最近确定了一组有效的和专有的TAK 1抑制剂化合物。从这一点出发，CLS建议开发TAK 1候选药物，重点关注以下具体目标：（1）优化两种TAK 1抑制剂先导系列的药物特性，并确定它们在阻断小鼠CAPS骨髓源性巨噬细胞（BMDM）和CAPS患者外周血单核细胞（PBMC）中IL-1 β、IL-18和NLRP 3生物合成以及IL-1 β信号转导方面的功效，以及（2）确定TAK 1候选药物在鼠NOMID模型中的功效。SBIR II期研究将重点关注产品开发和通过CAPS患者的人体I期临床评价推进该项目。支持性研究将包括监管毒理学、药代动力学和制剂合成。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证。在这个阶段，资产的商业交易在业内是非常有先例的，通常总额超过1亿美元。鉴于对CAPS有效治疗的巨大需求，开发安全的TAK 1抑制剂候选药物将产生重大的医学影响。

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.