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

TK216是一种研究性的、可能是一流的靶向小分子，旨在专门 抑制Ets家族癌蛋白的生物活性。涉及ETS因子的致癌基因融合 常见于肿瘤，如尤文肉瘤(ES)以及儿童白血病和前列腺癌 癌症。Ets因子在其他肿瘤中也经常过度表达，如神经母细胞瘤、淋巴瘤、急性 髓系白血病和高级别胶质瘤脑瘤。基于我们合作者实验室的工作 杰弗里·托雷斯基(乔治城大学)，Onctal Treeutics，Inc.发明了新型ETS家族抑制剂 TK216。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 A(RHA)导致转录变化和细胞凋亡。Onctal目前正在招募患有 复发或难治性ES，一种罕见的儿科癌症，历来难以有效治疗， 在一期临床试验中。中期分析显示，TK216总体耐受性良好，但有剂量限制 毒性为可控的骨髓抑制，无明显的靶外毒性。值得注意的是，目前的剂量 方案在7名可评估的患者中显示出早期令人兴奋的活动证据，其中1例手术完成。 完全缓解(CR)1例，部分缓解(PR)1例，肿瘤缩小90%。TK216已收到《孤儿》 美国食品和药物管理局(FDA)对治疗糖尿病的药物和快速通道指定 复发/难治性ES。ES由EWS-ETS融合蛋白驱动，融合蛋白通过相互作用发生 染色体易位。EWS-ETS融合蛋白被认为是不能下药的。然而， EWS-FLI1的作用机制是通过与其他蛋白质的配对来驱动的，因此TK216与YK-4-279类似， 通过破坏或阻止蛋白质-蛋白质相互作用(PPI)来针对EWS-ETS。鉴于这一重大需求 对于EWS-ETS靶向治疗，通过将TK216作为 通过门诊泵持续输液超过14天。这允许复发的ES患者获得访问权限 并提供有效的证据。虽然目前的这种给药形式对于患有 癌症很少或没有其他治疗选择，这对ES构成了严重的不便障碍 并有效防止其在ETS驱动的其他未得到满足的医疗需求中的临床应用- 监管失调。因此，我们提出两个主要目标，以支持以TK216为基础的 治疗：a)TK216针对ETS转录因子成员的活性谱的描绘 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生产。我们对于ES的意图是为ES患者提供更方便的给药形式，并 以便将TK216研究扩展到其他肿瘤学适应症。这个项目的首要目标是 是完成口服配方的开发并获得支持研究的临床前数据 新药(IND)申请扩大适应症。

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.