Development of TAK1 Inhibitors to Treat Pancreatic Cancer

描述（由申请人提供）：胰腺癌（PC）是美国癌症死亡的第四大原因。这种疾病的治疗选择非常有限，预后很差。目前，不到6%的PC患者在五年后仍然存活，诊断后的平均生存时间为4-6个月，这是所有癌症中最低的。显然，迫切需要新的治疗方法。组成型活性KRAS存在于几乎所有胰腺肿瘤中。尽管经过数十年的研究和大量的临床试验，抑制KRAS功能的新疗法一直不成功，将注意力转向下游的替代干预点。新出现的数据表明，TAK 1是KRAS功能的关键下游效应子，降低TAK 1表达或功能均导致胰腺肿瘤细胞系的细胞溶解和化疗吉西他滨的作用增强。这表明TAK 1是治疗PC的潜在药物靶点。我们不知道任何TAK 1候选药物正在开发中。在该SBIR I期中，Confluence Life Sciences（CLS）建议开发一种用于治疗PC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），该平台利用我们专有的亲电激酶抑制剂库进行基于结构的药物设计，以快速识别和开发活性的药物样化学核心为先导物质。KINect平台的创新性在行业中是独一无二的，将大大缩短临床候选人识别的时间轴，并增加成功的可能性。使用这种方法，CLS最近确定了一种有效的专有TAK 1抑制剂先导化合物CDD-162。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）使用基于结构的药物设计，将目前的专利先导物优化为2-3种选择性的、生物可利用的候选药物，其是TAK 1的有效抑制剂，（2）确定TAK 1抑制剂在基因型特征化的人PC细胞系中的功效，和（3）在使用人和小鼠PC肿瘤的小鼠模型中测定TAK 1抑制剂的功效。SBIR 2期研究将侧重于产品开发。该提案将通过PC患者的人类I期临床评价推进该项目。本临床研究将由我们的合作者大卫莱恩汉博士（华盛顿大学医学院）协调。支持性研究将包括体内毒理学、PK和其他体内癌症疗效模型。候选药物产品将引起癌症药物公司的极大兴趣，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PC有效治疗的巨大需求，我们相信开发安全的TAK 1抑制剂候选药物将产生重大的医学影响。

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is the fourth leading cause of death from cancer in the US. Treatment options for this disease are extremely limited and prognosis is poor. At present, less than 6% of PC patients are alive after five years with an average survival time following diagnosis of 4-6 months, which is among the lowest for all cancers. It is clear that new therapies are urgently needed. Constitutively active KRAS is present in virtually all pancreatic tumors. Despite decades of work and numerous clinical trials, new therapies to inhibit the function of KRAS have been uniformly unsuccessful turning attention downstream for alternative points of intervention. Emerging data implicate TAK1 as a key downstream effector of KRAS function and reducing TAK1 expression or function both resulted in cytolysis of pancreatic tumor cell lines and potentiation of the effect of the chemotherapeutic gemcitabine. This establishes that TAK1 is a potential drug target for the treatment of PC. We are not aware of any TAK1 drug candidates in development. In this SBIR Phase I Confluence Life Sciences (CLS) proposes to develop a proprietary TAK1 inhibitor drug candidate for the treatment of PC. CLS has developed an innovative kinase drug discovery platform (KINect) that exploits our proprietary electrophilic kinase inhibitor library in the contet of structure-based drug design to rapidly identify and develop active, drug-like chemical cores into lead matter. The innovative nature of the KINect platform is unique in the industry and will significantly shorten the timeline for clinical candidate identification and increase the probabiliy of success. Using this approach CLS has recently identified a potent, proprietary TAK1 inhibitor lead compound, CDD-162. From this starting point, CLS proposes to develop TAK1 drug candidates focusing on the following specific aims: (1) using structure-based drug design, optimize current proprietary leads into 2-3 selective, bioavailable drug candidates that are effective inhibitors of TAK1, (2) determine the efficacy of TAK1 inhibitors in genotypically characterized human PC cell lines, and (3) determine TAK1 inhibitor efficacy in mouse models using human and mouse PC tumors. SBIR phase 2 studies will focus on product development. This proposal will advance the program through human Phase 1 clinical evaluation in PC patients. This clinical study will be coordinated by our collaborator, Dr David Linehan (Washington University Medical School). Supporting studies will include in vivo toxicology, PK and additional in vivo cancer efficacy models. The drug candidate product will be of great interest to cancer drug companies and we anticipate a co- development partnership license. Commercial deals for assets at this stage are highly precedent in the industry and typically total >$100M. Given the great need for an effective therapeutic for PC we believe that the development of a safe TAK1 inhibitor drug candidate will have a major medical impact.