First-in-class ETS inhibitor TK216: Translational Biology and Oral Dosage Form Development

一流的 ETS 抑制剂 TK216：转化生物学和口服剂型开发

• 批准号: 10259473
• 负责人: Gunnar Joerg Floris Kaufmann
• 金额: $ 92.56万
• 依托单位: ONCTERNAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259473
• 关键词: Acute Myelocytic Leukemia; Address; Apoptosis; Biochemical; Biological; Biological Availability; Biology; Brain Neoplasms; Canis familiaris; Cardiopulmonary; Childhood Leukemia; Chimeric Proteins; Chromosomal translocation; Clinical Research; Clinical Trials; Continuous Infusion; Data; Development; Development Plans; Dosage Forms; Dose; Dose-Limiting; EWS-FLI1 fusion protein; Enrollment; Evaluable Disease; Ewings sarcoma; Family; Family member; Fatigue; Fertility; Formulation; Future; Gastrointestinal tract structure; Gene Fusion; Genetic Transcription; Glioma; Goals; Hair; In Vitro; In complete remission; Industry; Investigation; Investigational Drugs; Investigational New Drug Application; Laboratories; Liquid substance; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Musculoskeletal; Mutation; Myelosuppression; Nausea and Vomiting; Neuroblastoma; Oncology; Oncoproteins; Operative Surgical Procedures; Oral; Orphan Drugs; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Plan B; Pre-Clinical Model; Productivity; Protein Family; Proteins; Publications; Pump; RNA helicase A; Radiation; Records; Refractory; Regimen; Regulatory Affairs; Relapse; Research; Solid; Specificity; Sterility; Survivors; Tablets; Therapeutic; Toxic effect; Toxicology; United States Food and Drug Administration; Universities; Work; acute toxicity; analog; anticancer activity; base; biomarker discovery; clinical application; clinical development; design; drug mechanism; efficacy study; enzyme activity; in vivo; inhibitor/antagonist; meetings; member; model development; mouse model; novel; overexpression; partial response; patient derived xenograft model; potential biomarker; pre-clinical; prevent; programs; protein protein interaction; small molecule; standard of care; targeted treatment; transcription factor; tumor; tumor growth; tumorigenic

TK216 is an investigational, potentially first-in-class, targeted small molecule that is designed to specifically inhibit the biological activity of the ETS family of oncoproteins. Tumorigenic gene fusions involving ETS factors are frequently found in tumors, such as Ewing sarcoma (ES) as well as childhood leukemias and prostate cancer. ETS factors are also often overexpressed in other tumors, such as neuroblastoma, lymphomas, acute myeloid leukemia and high-grade glioma brain tumors. Based on work in the laboratory of our collaborator Jeffrey Toretsky (Georgetown University), Oncternal Therapeutics, Inc. created the novel ETS family inhibitor TK216. In preclinical models, TK216 inhibits the interaction between ETS family members and RNA helicase A (RHA) leading to transcriptional changes and apoptosis. Oncternal is currently enrolling patients with relapsed or refractory ES, a rare pediatric cancer that has historically been very challenging to treat effectively, in a Phase 1 clinical trial. Interim analysis has shown TK216 to be generally well-tolerated, with dose limiting toxicity of manageable myelosuppression and no obvious off-target toxicity. Notably, the current dosing regimen demonstrated early exciting evidence of activity in seven evaluable patients with 1 surgical complete response (CR) and 1 very good partial response (PR; 90% tumor shrinkage). TK216 has received Orphan Drug and Fast Track Designations from the U.S. Food and Drug Administration (FDA) for treatment of relapsed/refractory ES. ES is driven by an EWS-ETS fusion protein, which occurs through a reciprocal chromosomal translocation. The EWS-ETS fusion protein was considered ‘undruggable’. However, the mechanism of EWS-FLI1 is driven by its partnering with other proteins, thus TK216, similar to YK-4-279, targets the EWS-ETS by disrupting or preventing protein-protein interactions (PPI). Given the significant need for an EWS-ETS targeted therapy, the clinical development is being accelerated by administering TK216 as a continuous infusion via ambulatory pump over 14 days. This allowed relapsed ES patients to gain access and provide proof of efficacy. While this current form of administration is acceptable to patients suffering from cancers with few or no other treatment options available, it poses a significant inconvenience hurdle for ES patients as well as effectively prevents its clinical application in other unmet medical needs driven by ETS- dysregulation. Therefore, we propose 2 main objectives for our proposal to support the TK216-based therapies: a) delineation of the activity spectrum of TK216 against members of the ETS transcription factor family and b) development an oral dosing form of TK216, including GLP pharmacology/toxicology studies and GMP manufacturing. Our intent regarding ES is to offer a more convenient dosing form for ES patients and to allow for expansion of TK216 studies into other oncology indications. The overarching goal of this project is to complete the development of an oral formulation and obtain preclinical data supportive of Investigational New-Drug (IND) applications for indication expansion.

TK216是一种研究的，可能是一类靶向小分子，旨在专门设计 抑制ETS家族的生物学活性。涉及ETS因子的致瘤基因融合 经常在肿瘤中发现，例如尤因肉瘤（ES）以及儿童白血病和前列腺 癌症。 ETS因子在其他肿瘤中通常也过表达，例如神经母细胞瘤，淋巴瘤，急性 髓样白血病和高级神经胶质瘤脑肿瘤。基于我们合作者的实验室工作 Jeffrey Toretsky（乔治敦大学），Oncternal Therapeutics，Inc。创建了新颖的ETS家族抑制剂 TK216。在临床前模型中，TK216抑制ETS家族与RNA解旋酶之间的相互作用 A（RHA）导致转录变化和凋亡。 Oncterne目前正在注册患者 接力或耐火ES是一种罕见的儿科癌症，历史上一直受到有效治疗的挑战， 在1期临床试验中。临时分析表明TK216通常具有良好的耐受性，并具有剂量限制 可控制的骨髓抑制的毒性，没有明显的脱靶毒性。值得注意的是，当前剂量 方案表现出早期的令人兴奋的证据，表明七名具有1个手术完整的优秀患者的活动 反应（CR）和1个很好的部分反应（PR； 90％的肿瘤收缩）。 TK216已收到孤儿 美国食品药品监督管理局（FDA）的药物和快速轨道名称用于治疗 复发/难治性ES。 ES由EWS-ETS融合蛋白驱动，该蛋白通过倒数发生 染色体易位。 EWS-ETS融合蛋白被认为是“不可能的”。但是， EWS-FLI1的机制是由其与其他蛋白质合作的驱动的，因此TK216，类似于YK-4-279， 通过破坏或预防蛋白质 - 蛋白质相互作用（PPI）来靶向EWS-ET。考虑到很大的需求 对于针对EWSET的靶向疗法，通过管理TK216 AS来加速临床发展 通过门诊泵连续输注14天。这允许继电器ES患者进入 并提供效率证明。尽管这种当前的管理形式是可以接受的 癌症几乎没有或没有其他治疗方案，这给ES带来了重大不便 患者以及有效防止其在其他未满足医疗需求中的临床应用 - 失调。因此，我们为支持基于TK216的建议提出了2个主要目标 疗法：a）TK216对ETS转录因子成员的活性谱描述 家庭和b）开发TK216的口服剂量形式，包括GLP药理学/毒理学研究和 GMP制造。我们对ES的目的是为ES患者提供更方便的给药表格， 允许将TK216研究扩展到其他肿瘤学指示中。该项目的总体目标 是完成口服公式的开发并获得研究支持的临床前数据 新毒品（IND）的指示扩展应用程序。