Novel Compounds to Inactivate Oncogenic Fusion Proteins

灭活致癌融合蛋白的新型化合物

基本信息

批准号：
8403549
负责人：
JEFFREY A TORETSKY
金额：
$ 29.04万
依托单位：
GEORGETOWN UNIVERSITY
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：
2009-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403549
关键词：
3-Dimensional Address Adolescent Adverse effects Amino Acids Apoptosis Binding Biochemical Biochemistry Biological Assay Bone Marrow Transplantation Bone Tissue Cancer Patient Carcinoma Cell Death Cell Line Cells Cellular biology Characteristics Child Chimeric Proteins Chromosomal translocation Clinic Clinical Complex Developmental Therapeutics Program Disease Disease-Free Survival Dose Drug Design EWS-FLI1 fusion protein Ewings sarcoma FLI1 gene Family Family member Future Gene Expression Genetic Transcription Gold Growth Health Investigation Knowledge Lead Libraries Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Metastatic Ewing&apos s Sarcoma Molecular Biology Molecular Profiling Molecular Target Morbidity - disease rate Non-Malignant Oncogenes Oncogenic Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Property Proteins RNA helicase A Reagent Recurrent disease Regimen Reporter Research Resistance Series Specificity Structure Targeted Fusion Protein Therapy Testing Therapeutic Agents Toxic effect Transcription Coactivator Work Xenograft Model Xenograft procedure base beta pleated sheet bone cDNA Arrays cell growth cell motility chemotherapy chromatin immunoprecipitation design drug discovery improved inhibitor/antagonist killings leukemia malignant phenotype mathematical model mortality neoplastic cell novel novel therapeutic intervention novel therapeutics outcome forecast peptide A prevent protein function protein protein interaction research study response sarcoma screening small molecule soft tissue success transcription factor tumor tumor growth young adult

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy-resistant leukemias and sarcomas contain tumor-specific chromosomal translocations that encode fusion-proteins and these fusion-proteins are expressed only in the tumor. A fusion-protein provides significant tumor target specificity and increases the likelihood that novel therapies targeting the fusion-protein will be both effective and lack non-specific toxicity. Many of the tumor-specific fusion-proteins that function as transcription factors are disordered proteins. Disordered proteins lack the rigid alpha-helical or beta sheet structures required for structure-based drug design. While disordered proteins require a more empiric approach to the discovery of small molecule protein-protein interaction inhibitors, the biochemical properties of disordered proteins may actually favor the success of protein-protein interaction inhibitors. We will develop a novel paradigm to inhibit the protein-protein interaction of an oncogenic fusion protein. The Ewing's Sarcoma Family of Tumors (ESFT) contains a characteristic translocation, t(11:22), which leads to the oncogenic, fusion-protein, transcription factor EWS-FLI1. Therapies that inactivate EWS-FLI1 might address the significant problem of recurrent disease for patients. Since EWS-FLI1 lacks intrinsic enzymatic activity, and is a disordered protein, we will create novel protein-protein interaction inhibitors to block EWS-FLI1 binding to critical protein partners. We identified RNA Helicase A (RHA, p150), a DEAD/H family member that modulates gene expression, as a critical partner of EWS-FLI1. EWS-FLI1 binds to a unique region of RHA that is NOT involved in non-malignant RHA transcriptional modulation. A peptide mimic of this binding region inhibits EWS- FLI1 binding to RHA and we have discovered a lead compound, NSC635437, which has significant structural homology with the peptide mimic. A derivative small molecule of NSC635437, YK-4-279, blocks RHA binding to EWS-FLI1 and induces apoptosis in ESFT cells. We hypothesize that the interaction of RHA with EWS- FLI1 results in a potent transcriptional activator/coactivator complex, which amplifies the functions of both proteins and drives the malignant phenotype of ESFT. Our approach will develop reagents that prevent the binding of EWS-FLI1 to RHA, both to address our hypothesis and create a new therapeutic agent. We will accomplish our objectives by examining the effects of blocking RHA from enhancing EWS-FLI1 function, first using a peptide and then with small molecule protein-protein interaction inhibitors. We will work together with Dr. Milton Brown, a highly regarded medicinal chemist, to chemically optimize our lead compound. Our work has broad applicability to a larger group of tumors, serving as a new paradigm for developmental therapeutics. This paradigm to create small molecule inhibitors of EWS-FLI1 could be used for other translocation-defined malignancies such as chemotherapy-resistant carcinomas, sarcomas and leukemias. Therefore, future work would have a strong potential for a positive impact upon many patients with difficult to treat tumors leading to reduced mortality and morbidity.

描述（由申请人提供）：化疗耐药性白血病和肉瘤含有编码融合蛋白的肿瘤特异性染色体易位，并且这些融合蛋白仅在肿瘤中表达。融合蛋白提供了显着的肿瘤靶标特异性，并增加了靶向融合蛋白的新疗法既有效又缺乏非特异性毒性的可能性。许多充当转录因子的肿瘤特异性融合蛋白是无序蛋白。无序蛋白质缺乏基于结构的药物设计所需的刚性α螺旋或β折叠结构。虽然无序蛋白质需要更经验性的方法来发现小分子蛋白质-蛋白质相互作用抑制剂，但无序蛋白质的生化特性实际上可能有利于蛋白质-蛋白质相互作用抑制剂的成功。我们将开发一种新的范例来抑制致癌融合蛋白的蛋白质-蛋白质相互作用。尤文氏肉瘤肿瘤家族 (ESFT) 包含一个特征性易位 t(11:22)，它会产生致癌的融合蛋白转录因子 EWS-FLI1。灭活 EWS-FLI1 的疗法可能会解决患者疾病复发的重大问题。由于 EWS-FLI1 缺乏内在的酶活性，并且是一种无序蛋白质，因此我们将创建新型蛋白质-蛋白质相互作用抑制剂来阻止 EWS-FLI1 与关键蛋白质伴侣的结合。我们确定了 RNA 解旋酶 A (RHA，p150)（一种调节基因表达的 DEAD/H 家族成员）作为 EWS-FLI1 的关键伙伴。 EWS-FLI1 与 RHA 的一个独特区域结合，该区域不参与非恶性 RHA 转录调节。该结合区域的肽模拟物抑制 EWS-FLI1 与 RHA 的结合，我们发现了一种先导化合物 NSC635437，它与肽模拟物具有显着的结构同源性。 NSC635437 的衍生小分子 YK-4-279 可阻断 RHA 与 EWS-FLI1 的结合并诱导 ESFT 细胞凋亡。我们假设 RHA 与 EWS-FLI1 的相互作用产生有效的转录激活剂/共激活剂复合物，该复合物放大了两种蛋白的功能并驱动 ESFT 的恶性表型。我们的方法将开发阻止 EWS-FLI1 与 RHA 结合的试剂，这既是为了解决我们的假设，也是为了创造一种新的治疗剂。我们将通过检查阻断 RHA 增强 EWS-FLI1 功能的效果来实现我们的目标，首先使用肽，然后使用小分子蛋白质-蛋白质相互作用抑制剂。我们将与备受推崇的药物化学家 Milton Brown 博士合作，对我们的先导化合物进行化学优化。我们的工作对更多的肿瘤具有广泛的适用性，成为发育治疗的新范例。这种创建 EWS-FLI1 小分子抑制剂的范例可用于其他易位定义的恶性肿瘤，例如化疗耐药性癌、肉瘤和白血病。因此，未来的工作将对许多难以治疗的肿瘤患者产生积极影响，从而降低死亡率和发病率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer.

滑膜肉瘤是了解染色质重塑在癌症中的作用的途径。

DOI：
10.1007/s10555-015-9575-z
发表时间：
2015
期刊：
Cancer metastasis reviews
影响因子：
0
作者：
Zöllner,StefanK;Rössig,Claudia;Toretsky,JeffreyA
通讯作者：
Toretsky,JeffreyA

Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma.

DOI：
10.1158/1078-0432.ccr-09-2261
发表时间：
2010-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Erkizan HV;Uversky VN;Toretsky JA
通讯作者：
Toretsky JA