Novel Focal Adhesion Kinase autophosphorylation inhibitors against pancreatic cancer

描述(申请人提供)：由于缺乏有效的治疗方法，胰腺癌是导致男性和女性癌症死亡的第四大原因。本研究致力于开发以粘着斑激酶为靶点的抗胰腺癌新的小分子抑制剂。粘着斑激酶(FAK)已被证明在包括胰腺癌在内的肿瘤细胞存活中发挥重要作用，使FAK成为抗癌治疗的良好靶点。最近，本课题组开发了一种新型的小分子自磷酸化FAK抑制剂(1，2，4，5-苯四胺四胺盐酸盐)，它在体外直接特异性地降低FAK的自磷酸化，并显著抑制体内胰腺肿瘤的生长。Y15抑制剂有一种新的作用机制；与现有治疗方法相比，它的优势在于它针对的是 FAK。Y15具有高度特异性，无毒。该提案的目的是合成Y15的新型化学衍生物，以有效和特异性地抑制FAK自动磷酸化，目的是开发可用于未来临床前和临床试验的治疗方法。 治疗胰腺癌。为了开发具有更高药理特性的新的FAK抑制剂，我们将合成聚焦文库，通过多次试验进行筛选，以确定具有最佳生物学和药理特性的Y15衍生物。第一个目标是合成小分子FAK抑制剂Y15的化学衍生物，用于结构、活性关系研究和药理优化。第二个目的是测试这些新型抑制剂在体外对FAK自磷酸化活性的特异性和有效性，并测试它们抑制胰腺癌和癌症干细胞活性、克隆形成、肿瘤STM球形成、运动和侵袭的能力，以及诱导细胞周期停滞和凋亡的能力。第三个目标是进行ADMET和PK研究，以开发具有最佳药理特性的新的FAK抑制剂。其结果是在未来的临床前和临床试验中获得在阻断FAK活性和阻断胰腺癌和癌症干细胞功能方面具有最高效率的领先的新型Y15衍生物。这项研究将在该领域产生强大的影响，导致开发出具有最佳药理特性的新型小分子FAK抑制剂来阻断胰腺癌和癌症干细胞。拟议的项目是罗斯威尔公园癌症研究所和CureFAKtor制药公司的药物化学家、结构生物学家、生物化学家和肿瘤学家的综合努力，以开发针对胰腺癌的新型FAK靶向疗法。

DESCRIPTION (provided by applicant): Due to the absence of effective therapies, pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. This study focuses on the development of new small molecule inhibitors targeting Focal Adhesion Kinase against pancreatic cancer. Focal Adhesion Kinase (FAK) has been shown to play an important role in tumor cell survival, including pancreatic cancer, making FAK an excellent target for anti- cancer therapy. Recently, a novel small molecule autophosphorylation FAK inhibitor (1,2,4,5- Benzenetetraamine tetrahydrochloride) called Y15 has been developed by our group that directly and specifically decreased FAK autophosphorylation in vitro and significantly inhibited pancreatic tumor growth in vivo. Y15 inhibitor has a novel mechanism of action; its advantage over existing therapeutic approaches is that that it targets the autophosphorylation site (Y397) of FAK. Y15 is highly specific and non-toxic. The objective of the proposal is to synthesize the novel chemical derivatives of Y15 to effectively and specifically inhibit FAK autophosphorylation, with the aim of developing therapies that can be used in future pre-clinical and clinical trials to treat pancreatic cancer. To develop new FAK inhibitors with increased pharmacological properties, we will synthesize focused libraries that will be screened by multiple tests to identif Y15 derivatives with the best biological and pharmacological properties. The first aim is to synthesize chemical derivatives of the small molecule FAK inhibitor Y15 for structure activity relationship studies and pharmacological optimization. The second aim is to test these novel inhibitors for specificity and efficacy on FAK autophosphorylation activity in vitro, and to test their ability to inhibit pancreatic cancer and cancer stem cell viability, clonogenicity, cancer stm sphere formation, motility, and invasion, and to induce cell cycle arrest and apoptosis. The third aim is to perform ADMET and PK studies to develop new FAK inhibitors with the best pharmacological properties. The outcome is to obtain the lead novel Y15 derivatives with the highest efficacy in blocking FAK activity and blocking pancreatic cancer and cancer stem cell functions for future pre-clinical and clinical trials. This study will have a strong impact on the field, leading to the development of novel small molecule FAK inhibitors with the best pharmacological properties to block pancreatic cancer and cancer stem cells. The proposed project is an integrated effort of medicinal chemists, structural biologists, biochemists and oncologists of Roswell Park Cancer Research Institute and CureFAKtor Pharmaceuticals to develop novel FAK-targeted therapies against pancreatic cancer.