Targeting CDK4 in TGS-B Inactivated Gastrointestinal Cancers

TGS-B 灭活胃肠道癌中靶向 CDK4

• 批准号: 8744873
• 负责人: E Premkumar Reddy
• 金额: $ 17.08万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744873
• 关键词: Accounting; Adverse effects; Animal Model; Antineoplastic Agents; Biological Models; CDC2 Protein Kinase; CDK2 gene; CDK4 gene; Cell Cycle; Cell Cycle Progression; Cell Cycle Proteins; Cell Death; Cell Proliferation; Cessation of life; Clinical Trials; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 2A; Development; Drug Kinetics; Evaluation; Exhibits; Family; G1 Phase; Growth; Heterozygote; Human; Incidence; Kinetics; Knock-out; Libraries; Light; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Molecular; Mus; Normal Cell; Pharmaceutical Preparations; Preventive; Primitive foregut structure; Role; Safety; Scaffolding Protein; Signal Transduction; Structure-Activity Relationship; TGFB1 gene; Testing; Therapeutic Agents; Treatment Protocols; Tumor Suppressor Proteins; base; cancer cell; cancer therapy; cell transformation; cross reactivity; drug candidate; drug discovery; flavopiridol; human TGFBR2 protein; inhibitor/antagonist; kinase inhibitor; neoplastic cell; novel; preclinical study; protein expression; response; small molecule; small molecule libraries; transcription factor; tumor

Recent studies have shown that TGF-B inhibits cell proliferation by blocking cell cycle progression at the G1 phase of the cell cycle and hence, is thought to function as a tumor suppressor protein. Most human cancers appear to have lost their growth-inhibitory response to TGF-B. Our preliminary studies show that foregut cancers with inactivation of TGF-B signaling express high levels of cyclin D1 and CDK4 levels, suggesting that the deregulated expression of these proteins may contribute to the development of these tumors. Flavopiridol, an established Cdk inhibitor used in treatment protocols for certain cancers, is known to inhibit most known CDKs especially against CDKs 7, 8 and 9, is thought to be largely responsible for the toxic side effects caused by this drug in clinical trials. In light of these observations, we have screened a compound library of kinase inhibitors for CDK-4 specific inhibition and isolated two novel molecules (ON55290 and ON27900) which exhibit CDK4 inhibitory activity. In this application, we propose to carry out pre-clinical studies to test the usefulness of these molecules in gastrointestinal cancer therapy. The aims of the proposal are: 1. To further validate the role of CDK4 in Elf+/-, Elf+/-:Smad3+/- tumor model system through evaluation of tumor incidence in CDK4+/V El+/- : CDK4+/-: Elf/Elf[+]-Smad4[+/-] and CDK4[+/-]; Elf¿/Elf+:Smad4+/- mice. 2. (a) To expand the chemical library in an effort to understand the structure-activity relationship (SAR) of CDK4 inhibitors and (b) to conduct a detailed kinetic analysis of CDK4 inhibition by ON55290 and ON27900 to gain critical information on the mechanisms by which these compounds elicit their inhibitory effects on CDK4. 3. To determine the molecular mechanisms by which ON55290 and ON27900 bring about growth arrest and death of human gastrointestinal cancer cells. 4. To assess the safety and pharmacokinetics of the candidate drug in animal models of gastrointestinal cancers that develop in the TGF-f3 inactivated state.

最近的研究表明，TGF-B通过在细胞周期的G1阶段阻断细胞周期进程而抑制细胞增殖，因此被认为是肿瘤抑制蛋白的作用。大多数人类癌症似乎失去了对TGF-B的抑制作用。我们的初步研究表明，前肢癌症失活了TGF-B信号表达高水平的细胞周期蛋白D1和CDK4水平，这表明这些蛋白质的失调表达可能有助于这些肿瘤的发展。葡萄肽是用于某些癌症治疗方案中的一种已建立的CDK抑制剂，已知可以抑制最已知的CDK，尤其是对CDKS 7、8和9的抑制作用，被认为在很大程度上是造成该药物在临床试验中引起的毒性副作用的造成的。鉴于这些观察结果，我们筛选了一个用于CDK-4特异性抑制的激酶抑制剂的复合库，并分离了两个新的分子（ON55290和27900），该分子暴露了CDK4抑制作用。在此应用中，我们建议进行临床前研究，以测试这些分子在胃肠道癌症治疗中的有用性。该提案的目的是： 1。为了进一步验证CDK4在ELF +/-，ELF +/-：SMAD3 +/-：SMAD3 +/-：通过评估CDK4+/V EL +/-：CDK4 +/-：ELF/ELF [+] -SMAD4 [+/-]和CDK4 [+/-]和CDK4 [+/-]; ELF¿ /ELF+：SMAD4 +/-鼠标。 2。（a）扩展化学文库，以了解CDK4抑制剂的结构 - 活性关系（SAR）和（b）以对ON55290和ON27900对CDK4抑制的详细动力学分析，以获取有关这些机制的关键信息，从而使这些机制对这些机制产生对CDK4的抑制作用。 3。确定ON55290和ON27900带来人类胃肠道癌细胞的生长停滞和死亡的分子机制。 4。评估候选药物在TGF-F3灭活状态中发展的胃肠道癌动物模型中的候选药物的安全性和药代动力学。