Novel Focal Adhesion Kinase autophosphorylation inhibitors against pancreatic cancer

针对胰腺癌的新型粘着激酶自磷酸化抑制剂

• 批准号: 8831067
• 负责人: Vita M Golubovskaya
• 金额: $ 21.95万
• 依托单位: CUREFAKTOR PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2014-12-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831067
• 关键词: Antibodies; Antineoplastic Agents; Apoptosis; Binding Sites; Biological; Biological Assay; Breast; Cancer Cell Growth; Cancer Etiology; Cell Cycle; Cell Cycle Arrest; Cell Line; Cell Survival; Cell physiology; Cessation of life; Chemicals; Clinical; Clinical Research; Clinical Trials; Colon; Data; Development; Diagnosis; Disease; Dose; Drug Kinetics; Excision; Excretory function; Focal Adhesion Kinase 1; Future; Glioblastoma; Goals; Growth; In Vitro; Lead; Libraries; Lung; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolism; Mus; Neoplasm Metastasis; Neuroblastoma; Oncologist; Operative Surgical Procedures; Outcome; Pancreas; Patients; Permeability; Pharmacologic Substance; Phase; Phosphorylation; Phosphotransferases; Play; Preclinical Testing; Property; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Public Health; Research Institute; Role; Signal Pathway; Site; Solid Neoplasm; Solubility; Specificity; Stream; Structural Biologist; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Toxicology; United States; Western Blotting; Woman; Xenograft Model; absorption; analytical method; anticancer research; base; cancer cell; cancer stem cell; cancer therapy; cancer type; cell motility; drug development; effective therapy; efficacy testing; in vitro activity; in vivo; inhibitor/antagonist; kinase inhibitor; men; method development; neoplastic cell; novel; outcome forecast; overexpression; pancreatic cancer cells; pancreatic cell line; pancreatic neoplasm; pre-clinical; programs; public health relevance; research clinical testing; screening; small molecule; small molecule libraries; stem; therapeutic target; therapy development; tumor; tumor growth

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.

描述（由申请人提供）：由于缺乏有效的治疗方法，胰腺癌是男性和女性癌症死亡的第四大原因。本研究的重点是开发新的靶向黏附激酶的小分子抑制剂来治疗胰腺癌。病灶黏附激酶（Focal Adhesion Kinase， FAK）在包括胰腺癌在内的肿瘤细胞存活中发挥着重要作用，使FAK成为抗癌治疗的一个很好的靶点。近年来，本研究组开发了一种新型的小分子自磷酸化FAK抑制剂（1,2,4,5-苯四胺四盐酸盐）Y15，在体外直接特异性降低FAK自磷酸化，在体内显著抑制胰腺肿瘤生长。Y15抑制剂具有新的作用机制；与现有的治疗方法相比，它的优势在于它靶向细胞的自磷酸化位点（Y397）