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 是一种正在研究的、可能是同类首创的靶向小分子，专门设计用于 抑制涉及 ETS 因子的致瘤基因融合的 ETS 家族的生物活性。 常见于肿瘤中，例如尤文肉瘤 (ES) 以及儿童白血病和前列腺 ETS 因子在其他肿瘤中也经常过度表达，例如神经母细胞瘤、淋巴瘤、急性肿瘤。 骨髓性白血病和高级别神经胶质瘤脑肿瘤基于我们合作者实验室的工作。 Oncternal Therapeutics, Inc. 的 Jeffrey Toretsky（乔治敦大学）创造了新型 ETS 家族抑制剂 在临床前模型中，TK216 抑制 ETS 家族成员与 RNA 解旋酶之间的相互作用。 Oncternal 正在招募导致转录变化和细胞凋亡的 A (RHA) 患者。 复发性或难治性 ES，一种罕见的儿科癌症，历来很难有效治疗， 一项 1 期临床试验显示 TK216 总体耐受性良好，但有剂量限制。 骨髓抑制的毒性是可控的，并且没有明显的脱靶毒性。值得注意的是，目前的剂量。 方案在 7 名可评估患者中显示出早期令人兴奋的活性证据，其中 1 名患者完成了手术 TK216 已获得 1 例缓解（CR）和 1 例非常好的部分缓解（PR；肿瘤缩小 90%）。 美国食品和药物管理局 (FDA) 指定用于治疗以下疾病的药物和快速通道指定 复发/难治性 ES 由 EWS-ETS 融合蛋白驱动，通过相互作用发生。 EWS-ETS 融合蛋白被认为是“不可成药的”。 EWS-FLI1 的机制是由其与其他蛋白质（例如 TK216，类似于 YK-4-279）的合作驱动的， 考虑到巨大的需求，通过破坏或阻止蛋白质-蛋白质相互作用（PPI）来瞄准 EWS-ETS。 对于 EWS-ETS 靶向治疗，通过施用 TK216 来加速临床开发 通过流动泵连续输注超过 14 天，这使得复发的 ES 患者能够获得治疗。 并提供疗效证明，而目前的给药方式对于患有此病的患者来说是可以接受的。 几乎没有或没有其他治疗选择的癌症，这给 ES 带来了显着的不便障碍 患者，并有效阻止其在 ETS 驱动的其他未满足的医疗需求中的临床应用- 因此，我们为支持基于 TK216 的提案提出了 2 个主要目标。 疗法：a) 描绘 TK216 针对 ETS 转录因子成员的活性谱 b) 开发 TK216 的口服剂型，包括 GLP 药理学/毒理学研究和 我们关于 ES 的 GMP 生产目的是为 ES 患者提供更方便的剂量形式。 将 TK216 研究扩展到其他肿瘤学适应症是该项目的总体目标。 是完成口服制剂的开发并获得支持研究的临床前数据 用于适应症扩展的新药 (IND) 申请。