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 期阻断细胞周期进程来抑制细胞增殖，因此被认为具有肿瘤抑制蛋白的功能。大多数人类癌症似乎已经失去了对 TGF-B 的生长抑制反应。我们的初步研究表明，TGF-B 信号失活的前肠癌表达高水平的细胞周期蛋白 D1 和 CDK4，这表明这些蛋白的表达失调可能有助于这些肿瘤的发展。 Flavopiridol 是一种用于某些癌症治疗方案的成熟 Cdk 抑制剂，已知可抑制大多数已知的 CDK，尤其是 CDK 7、8 和 9，被认为是该药物在临床试验中引起毒副作用的主要原因。根据这些观察结果，我们筛选了用于 CDK-4 特异性抑制的激酶抑制剂化合物库，并分离出两种具有 CDK4 抑制活性的新分子（ON55290 和 ON27900）。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效性。该提案的目的是： 1. 通过评估CDK4+/V El+/- : CDK4+/-: Elf/Elf[+]-Smad4[+/-]和CDK4[+/-]肿瘤发生率，进一步验证CDK4在Elf+/-、Elf+/-:Smad3+/-肿瘤模型系统中的作用； Elf¿/Elf+:Smad4+/- 小鼠。 2. (a) 扩展化学库，以了解 CDK4 抑制剂的构效关系 (SAR)；(b) 对 ON55290 和 ON27900 抑制 CDK4 进行详细的动力学分析，以获得这些化合物对 CDK4 产生抑制作用的机制的关键信息。 3. 确定ON55290和ON27900导致人胃肠道癌细胞生长停滞和死亡的分子机制。 4. 评估候选药物在TGF-f3失活状态下发生的胃肠癌动物模型中的安全性和药代动力学。