Multiple kinase target inhibition with EMND-2076 in multiple myeloma

EMND-2076 对多发性骨髓瘤的多激酶靶点抑制

• 批准号: 8013948
• 负责人: Sherif S Farag
• 金额: $ 31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013948
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aftercare; Alkylating Agents; Angiogenesis Inhibition; Angiopoietin-1; Apoptotic; Area Under Curve; Bioavailable; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Blood; Bone Marrow; Bortezomib; Cell Cycle Arrest; Cell Line; Cells; Cleaved cell; Clinical; Clinical Trials; Complex; Core Biopsy; Critical Pathways; Cytotoxic agent; Data; Development; Disease; Dose; Dose-Limiting; Down-Regulation; Drug Kinetics; Drug resistance; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Future; Growth; Half-Life; Health; Hematopoietic stem cells; Histones; Immunofluorescence Microscopy; In Vitro; In complete remission; Investigation; Laboratories; Laboratory Study; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Mitosis; Multiple Myeloma; Oral; Oral Administration; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Plasma; Proteins; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Refractory; Relapse; Reporting; Research; Resistance; Survival Rate; Testing; Thalidomide; Time; Tissues; Toxic effect; Vascular Endothelial Growth Factors; angiogenesis; angiogenin; aurora kinase; aurora-A kinase; base; conventional therapy; cytokine; cytotoxic; density; experience; fibroblast growth factor receptor 3; human BIRC4 protein; improved; in vivo; killings; kinase inhibitor; lenalidomide; novel; pre-clinical; preclinical study; response; survivin

DESCRIPTION (provided by applicant): Current therapy for multiple Myeloma (MM) remains unsatisfactory, and despite recent improvements in treatment, the disease remains incurable indicating the need for continued investigation of novel agents. We have investigated a novel agent, ENMD-2076, in MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with a complex mechanism of action, including antiproliferative and pro-apoptotic activity, and inhibition of angiogenesis. In preclinical studies, we have shown that ENMD-2076 has significant in vitro and in vivo activity against MM cell lines and primary MM cells, and targets multiple pathways critical to the growth and survival of myeloma cells. In addition to being cytotoxic to MM cells, we have shown that ENMD-2076 cleaves Mcl-1 and down regulates the anti-apoptotic proteins survivin and X-linked inhibitor of apoptosis (XIAP); inhibits the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, fibroblast growth factor receptor-3 (FGFR3) receptor tyrosine kinase activity, and the aurora kinases A and B, inducing cycle arrest in the G2/M phase cell; and inhibits of angiogenesis. The significant activity against MM cells, and the importance of the pathways targeted by this agent in the pathogenesis of MM, provides strong rationale for clinical development of ENMD- 2076 in MM. No clinical experience has been reported with ENMD-2076. Therefore, based on our laboratory studies we propose to initiate clinical investigation of ENMD-2076 in patients with MM. Specifically, we propose 1) to conduct a phase I trial to investigate the dose limiting toxicity and maximal tolerated dose of oral ENMD-2076 in patients with relapsed or refractory MM, 2) Describe the pharmacokinetic profile of ENMD-2076 following oral administration, and 3) Assess the in vivo biological activity of ENMD-2076 on important target pathways identified in our preclinical studies, and explore the feasibility of utilizing some of these as potential biomarkers for testing in future clinical trials that will assess efficacy. The results of this research will be important to the understanding of clinical mechanism of action of ENMD-2076 and its optimal use in future clinical investigation in MM, which has important significance for the outcome of this currently incurable disease.

描述（由申请人提供）：目前多发性骨髓瘤（MM）的治疗仍然不能令人满意，尽管最近治疗有所改善，但该疾病仍然无法治愈，表明需要继续研究新药。我们在 MM 中研究了一种新药物 ENMD-2076。 ENMD-2076 是一种口服生物可利用的多靶点激酶抑制剂，具有复杂的作用机制，包括抗增殖和促凋亡活性以及抑制血管生成。在临床前研究中，我们表明 ENMD-2076 对 MM 细胞系和原代 MM 细胞具有显着的体外和体内活性，并靶向对骨髓瘤细胞生长和存活至关重要的多种途径。除了对 MM 细胞具有细胞毒性外，我们还发现 ENMD-2076 可以裂解 Mcl-1 并下调抗凋亡蛋白 survivin 和 X 连锁凋亡抑制剂 (XIAP)；抑制磷脂酰肌醇 3 激酶 (PI3K)/Akt 通路、成纤维细胞生长因子受体 3 (FGFR3) 受体酪氨酸激酶活性以及极光激酶 A 和 B，诱导 G2/M 期细胞周期停滞；并抑制血管生成。针对 MM 细胞的显着活性，以及​​该药物针对的途径在 MM 发病机制中的重要性，为 ENMD-2076 在 MM 中的临床开发提供了强有力的理由。尚未报告 ENMD-2076 的临床经验。因此，根据我们的实验室研究，我们建议在 MM 患者中启动 ENMD-2076 的临床研究。具体来说，我们建议 1) 进行一项 I 期试验，以研究复发或难治性 MM 患者口服 ENMD-2076 的剂量限制毒性和最大耐受剂量，2) 描述口服给药后 ENMD-2076 的药代动力学特征，以及 3) 评估 ENMD-2076 对我们临床前研究中确定的重要靶标途径的体内生物活性，并探索 ENMD-2076 的体内生物活性。 利用其中一些作为潜在生物标志物在未来评估疗效的临床试验中进行测试的可行性。这项研究的结果对于了解 ENMD-2076 的临床作用机制及其在未来 MM 临床研究中的最佳使用具有重要意义，这对于这种目前无法治愈的疾病的结果具有重要意义。

项目成果

The potential role of Aurora kinase inhibitors in haematological malignancies.

• DOI: 10.1111/j.1365-2141.2011.08898.x
• 发表时间: 2011-12
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Farag SS