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Targeting CDK4 in TGS-B Inactivated Gastrointestinal Cancers

TGS-B 灭活胃肠道癌中靶向 CDK4

基本信息

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
项目类别：
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

项目摘要

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，转化生长因子-β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，因此被认为是一种肿瘤抑制蛋白。大多数人类癌症似乎已经失去了对转化生长因子-B的生长抑制反应。我们的初步研究表明，转化生长因子-B信号失活的前肠癌表达高水平的细胞周期蛋白D1和CDK4，提示这些蛋白的表达失控可能有助于肿瘤的发展。作为一种成熟的CDK抑制剂，用于某些癌症的治疗方案，已知可以抑制大多数已知的CDK，特别是对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。在这些观察的基础上，我们筛选了CDK-4特异性抑制的激酶抑制剂的化合物文库，并分离出了两个具有CDK4抑制活性的新分子(ON55290和ON27900)。在这一应用中，我们建议开展临床前研究，以测试这些分子在胃肠道癌症治疗中的有效性。这项建议的目的是： 1.通过对CDK4+/V EL+/-：CDK4+/-：Elf/Elf[+]-Smad4[+/-]和CDK4[+/-]；Elf+/Elf+：Smad4+/-小鼠肿瘤发生率的评价，进一步验证CDK4在Elf+/-、Elf+/-：Smad3+/-肿瘤模型系统中的作用。 2.(A)扩大化学库，以了解CDK4抑制剂的构效关系(SAR)；(B)对ON55290和ON27900对CDK4的抑制进行详细的动力学分析，以获得这些化合物对CDK4的抑制作用机制的关键信息。 3.探讨ON55290和ON27900诱导人胃肠道癌细胞生长停滞和死亡的分子机制。4.评价该候选药物在转化生长因子-f3失活的胃肠道肿瘤动物模型中的安全性和药代动力学。