Development of TAK1 Inhibitors to Treat Pancreatic Cancer

描述(申请人提供)：胰腺癌(PC)是美国第四大癌症死亡原因。这种疾病的治疗选择极其有限，预后也很差。目前，只有不到6%的PC患者在确诊后存活五年，平均生存时间为4-6个月，这在所有癌症中是最低的。显然，迫切需要新的治疗方法。成分活性KRAS几乎存在于所有胰腺肿瘤中。尽管几十年的工作和无数的临床试验，抑制KRAS功能的新疗法一直都没有成功，将注意力转向下游的替代干预点。新的数据表明，TAK1是KRAS功能的关键下游效应因子，降低TAK1的表达或功能都会导致胰腺癌细胞株的细胞溶解，并增强化疗药物吉西他滨的作用。这表明TAK1是治疗前列腺癌的潜在药物靶点。我们不知道有任何TAK1候选药物正在开发中。在这个SBIR第一阶段，汇流生命科学公司(CLS)提议开发一种治疗PC的TAK1抑制剂专利候选药物。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中利用我们专有的亲电激酶抑制剂库来快速识别和开发活性的、类药物的化学核心，并将其转化为铅物质。Kinect平台的创新性质在行业中是独一无二的，将大大缩短临床候选识别的时间线，并增加成功的可能性。使用这种方法，CLS最近发现了一种有效的、专有的TAK1抑制剂先导化合物CDD-162。从这一起点出发，CLS建议开发TAK1候选药物，专注于以下特定目标：(1)使用基于结构的药物设计，将现有的专有线索优化为2-3个选择性的、生物可利用的候选药物，这些候选药物是TAK1的有效抑制剂；(2)确定TAK1抑制剂在具有基因特征的人PC细胞系中的有效性；以及(3)利用人和小鼠PC肿瘤模型确定TAK1抑制剂的有效性。SBIR第二阶段的研究将集中在产品开发上。这项建议将通过对PC患者进行人类第一阶段临床评估来推进该计划。这项临床研究将由我们的合作者，华盛顿大学医学院的David Linehan博士协调。支持研究将包括体内毒理学、PK和其他体内癌症疗效模型。这种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。现阶段针对资产的商业交易在业内是极具先例的，通常总金额为1亿美元。鉴于对PC有效治疗的巨大需求，我们相信开发一种安全的TAK1抑制剂候选药物将对医学产生重大影响。

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.