Novel Compounds to Inactivate Oncogenic Fusion Proteins

灭活致癌融合蛋白的新型化合物

• 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
• 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' 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

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（申请人提供）：化疗耐药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，这些融合蛋白仅在肿瘤中表达。融合蛋白提供了显著的肿瘤靶特异性，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。许多作为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多的经验方法来发现小分子蛋白质-蛋白质相互作用抑制剂，但无序蛋白质的生物化学性质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。尤文氏肉瘤家族肿瘤（ESFT）包含一个特征性易位t（11：22），导致致癌融合蛋白转录因子EWS-FLI 1。抑制EWS-FLI 1的疗法可能会解决患者疾病复发的重要问题。由于EWS-FLI 1缺乏内在的酶活性，是一种无序的蛋白质，我们将创造新的蛋白质-蛋白质相互作用抑制剂来阻断EWS-FLI 1与关键蛋白质伴侣的结合。我们鉴定了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-FLI 1的关键伴侣。EWS-FLI 1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。该结合区的肽模拟物抑制EWS-FLI 1与RHA的结合，并且我们发现了与肽模拟物具有显著结构同源性的先导化合物NSC 635437。NSC 635437的衍生小分子YK-4-279阻断RHA与EWS-FLI 1的结合并诱导ESFT细胞凋亡。我们假设RHA与EWS-FLI 1的相互作用导致了一种有效的转录激活因子/共激活因子复合物，该复合物放大了两种蛋白质的功能并驱动了ESFT的恶性表型。我们的方法将开发阻止EWS-FLI 1与RHA结合的试剂，以解决我们的假设并创造一种新的治疗剂。我们将通过检查阻断RHA增强EWS-FLI 1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。我们将与米尔顿布朗博士合作，他是一位德高望重的药物化学家，对我们的先导化合物进行化学优化。我们的工作具有广泛的适用性，更大的一组肿瘤，作为一个新的范式发展治疗。这种产生EWS-FLI 1小分子抑制剂的范例可用于其他易位定义的恶性肿瘤，如化疗耐药癌、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

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
• 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
• 作者: Erkizan HV;Uversky VN;Toretsky JA
• 通讯作者: Toretsky JA