CDK3-inhibiting anticancer agents

CDK3抑制抗癌药物

基本信息

批准号：
8339426
负责人：
Donald C. Porter
金额：
$ 47.39万
依托单位：
SENEX BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8339426
关键词：
Affect Animals Antibodies Antineoplastic Agents Apoptosis Apoptotic Binding Biological Assay Brain Brain Neoplasms CDC2 Protein Kinase CDK2 gene CDK3 gene CDK4 gene Cancer Model Cell Culture Techniques Cell Cycle Cell Line Clinical Colon Carcinoma Computer Simulation Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Development Disease Docking Dose Drug Design Drug Kinetics Drug usage Family Gene Expression Microarray Analysis Generations Genes Glioblastoma Goals Grant Human Implant In Vitro Induction of Apoptosis Injection of therapeutic agent Laboratory mice Lead Malignant Epithelial Cell Malignant Neoplasms Measures Mediating Modeling Morphology Normal Cell Nude Rats Oncogenes Oral Palpable Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Plasma Plasma Proteins Play Poison Predisposition Production Protein Binding Proteins Proteolysis RNA Radiation Rattus Relative (related person)Role Safety Small Business Innovation Research Grant Solubility Staging Structural Models Structure Synthesis Chemistry Testing Time Toxic effect Transcription Factor AP-1 Tumor Cell Line Tumor Suppression Tumor Volume Variant Xenograft Model Xenograft procedure angiogenesis anticancer activity base cell growth chemical synthesis chemotherapy cytokine fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether human tissue improved in vitro Assay in vitro testing in vivo inhibitor/antagonist killings member neoplastic cell novel overexpression paracrine phase 2 study potency testing pre-clinical preclinical study programs research clinical testing research study temozolomide transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): This Phase II SBIR project is aimed at developing a novel type of drugs, termed SNX9-class compounds, with a unique combination of two anticancer activities. The first is a selective antiproliferative effect on tumor cells relative to normal cells. The second is the inhibition of chemotherapy- or radiation-induced expression of multiple genes encoding secreted tumor-supporting factors with mitogenic, antiapoptotic and angiogenic activities; as a result, SNX9-class compounds potentiate the induction of apoptosis by conventional chemotherapeutic drugs. Studies conducted during Phase I of this project showed that both activities of SNX9- class compounds are due to their ability to inhibit CDK3. This understudied member of the cyclin-dependent kinase (CDK) family is apparently unneeded by normal cells, based on its very low expression in normal human tissues and spontaneous germline inactivation in laboratory mice. However, CDK3 is overexpressed in different cancers, where it acts as an oncogene enhancing the activity of transcription factor AP1 (Jun/Fos). This tumor selectivity advantageously distinguishes CDK3 as a cancer target from cell cycle-regulating CDKs (CDK1, CDK2, CDK4/6), which are targeted by pharmaceutical CDK inhibitors, previously developed by others. Computer modeling and structure-activity analysis conducted during Phase I indicate that SNX9-class compounds selectively inhibit CDK3 through binding to a newly identified allosteric pocket that distinguishes CDK3 from the closely related CDK2 and other CDKs. The first aim of the proposed Phase II study is to develop new, more potent and selective SNX9-class CDK3 inhibitors through rational drug design, based on computer modeling of SNX9-CDK3 interactions. The second aim is to test the effects of SNX9-class compounds on the production of multiple tumor-supporting secreted factors by chemotherapy- and radiation- damaged tumor cells, at the levels of RNA, protein, and paracrine anti-apoptotic activity. The third aim is to test SNX9-class compounds for their antiproliferative activity in different colon carcinoma and glioblastoma cell lines, the tumor types that are indicated by CDK3 expression and inhibition assays to be most likely to be susceptible to CDK3 inhibitors. The fourth aim is to evaluate SNX9-class compounds that show in vitro potency and CDK3 selectivity by assessments of in vivo toxicity and pharmacokinetics in rats (which, unlike laboratory mice, express functional CDK3). The results of these assessments will be used to select the compound with the most favorable pharmacokinetics and the least toxicity for in vivo efficacy studies, which constitute the fifth and the final aim of this proposal. In vivo tumor-suppression studies will be conducted in rat xenograft models of human colon carcinoma and glioblastoma (intracranial model). A compound showing safety and efficacy in vivo will be selected for preclinical and clinical development as a new anticancer drug.

描述（由申请人提供）：此II期SBIR项目旨在开发一种新型的药物，称为SNX9级化合物，具有两种抗癌活性的独特组合。第一个是相对于正常细胞的肿瘤细胞的选择性抗增殖作用。第二个是抑制化学疗法或辐射诱导的多种基因表达，这些基因编码有丝分裂，抗凋亡和血管生成活性的分泌肿瘤支持因子。结果，SNX9级化合物增强了传统化学治疗药物诱导凋亡的诱导。在该项目的第一阶段进行的研究表明，SNX9类化合物的两种活性都是由于它们抑制CDK3的能力。基于正常细胞在正常的人体组织中表达非常低的表达和实验室小鼠的自发生殖灭活，这显然不需要细胞细胞周期依赖性激酶（CDK）家族的研究。但是，CDK3在不同的癌症中过表达，在不同的癌症中，它充当了一种增强转录因子AP1活性（JUN/FOS）的活性。这种肿瘤选择性有利地将CDK3与细胞周期调节的CDK（CDK1，CDK2，CDK4/6）区分开，该癌症是由其他人先前开发的药物CDK抑制剂靶向的。在第一阶段进行的计算机建模和结构活性分析表明，SNX9级化合物通过结合与新近鉴定的变构袋有选择性地抑制CDK3，该袋将CDK3与紧密相关的CDK2和其他CDK区分开。拟议的II期研究的第一个目的是基于SNX9-CDK3相互作用的计算机建模，通过合理的药物设计开发了新的，更有效，更有效的SNX9级CDK3抑制剂。第二个目的是在RNA，蛋白质和旁分泌抗凋亡活性的水平下测试SNX9级化合物对通过化学疗法和放射受损的肿瘤细胞产生多种肿瘤支出因子的影响。第三个目的是测试SNX9级化合物在不同结肠癌和胶质母细胞瘤细胞系中的抗增生活性，这是CDK3表达和抑制测定最有可能对CDK3抑制剂敏感的肿瘤类型。第四个目的是评估SNX9级化合物，这些化合物通过评估大鼠体内毒性和药代动力学的评估（与实验室小鼠不同，表达功能性CDK3）来显示体外效力和CDK3选择性。这些评估的结果将用于选择具有最有利的药代动力学的化合物，并且对体内功效研究的毒性最少，这构成了该提案的第五和最终目的。体内肿瘤抑制研究将在人类结肠癌和胶质母细胞瘤的大鼠异种移植模型（颅内模型）中进行。将选择显示体内安全性和功效的化合物作为一种新的抗癌药物，以用于临床前和临床发育。