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

TK216是一种研究性的、潜在的一流的靶向小分子，其被设计为特异性地 抑制癌蛋白ETS家族的生物活性。涉及ETS因子的致瘤基因融合 经常在肿瘤中发现，如尤文肉瘤（ES）以及儿童白血病和前列腺癌。 癌ETS因子也经常在其他肿瘤中过表达，如神经母细胞瘤、淋巴瘤、急性淋巴细胞瘤和急性淋巴细胞瘤。 骨髓性白血病和高级别神经胶质瘤。基于我们的合作者在实验室的工作 Jeffrey Toretsky（乔治敦大学），Oncternal Therapeutics，Inc.创造了新的ETS家族抑制剂 TK216在临床前模型中，TK 216抑制ETS家族成员与RNA解旋酶之间的相互作用 A（RHA）导致转录变化和凋亡。Oncternal目前正在招募以下患者： 复发性或难治性ES是一种罕见的儿科癌症，在历史上一直很难有效治疗， 在一个临床试验阶段。中期分析显示TK216通常耐受良好，剂量限制 骨髓抑制毒性可控，无明显脱靶毒性。值得注意的是，目前的剂量 方案在7例可评价患者中显示了早期令人兴奋的活性证据，其中1例手术完成 结果显示，1例患者获得了完全缓解（CR），1例患者获得了非常好的部分缓解（PR; 90%肿瘤缩小）。TK216已接收孤儿 美国食品药品监督管理局（FDA）的药物和快速通道指定，用于治疗 复发性/难治性ES。ES由EWS-ETS融合蛋白驱动，其通过相互作用发生。 染色体易位EWS-ETS融合蛋白被认为是"不易碎的"。但 EWS-FLI1的机制是由其与其他蛋白质的伙伴关系驱动的，因此TK216，类似于YK-4 - 279， 通过破坏或阻止蛋白质-蛋白质相互作用（PPI）靶向EWS-ETS。考虑到大量的需求 对于EWS-ETS靶向治疗，通过给予TK216作为 通过流动泵持续输注14天。这使得复发的ES患者能够获得 并提供有效性证明。虽然这种目前的给药形式对于患有糖尿病的患者是可接受的， 在几乎没有或没有其他治疗选择的情况下，它对ES构成了重大的不便障碍。 患者，并有效地防止其在ETS驱动的其他未满足的医疗需求中的临床应用- 失调因此，我们提出了两个主要目标，以支持基于TK 216的 a）描绘TK 216针对ETS转录因子成员的活性谱 家族和B）开发TK 216的口服给药形式，包括GLP药理学/毒理学研究，以及 GMP生产。我们关于ES的目的是为ES患者提供更方便的给药形式， 允许将TK 216研究扩展到其他肿瘤适应症。这个项目的首要目标是 是完成口服制剂的开发，并获得支持研究的临床前数据 新药（IND）适应症扩展申请。

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.