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

基本信息

批准号：
10473797
负责人：
Rajesh Krishnan
金额：
$ 102.32万
依托单位：
ONCTERNAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473797
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 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

项目摘要

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，具有预算的一流的，有针对性的小分子，旨在专门设计抑制肿瘤蛋白的ETS家族的生物学活性。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 ETS因子在其他肿瘤中也过表达基于我们合作者的工作，髓样白血病和高级神经胶质瘤 Jeffrey Toretsky（乔治敦大学），Oncternal Therapeutics，Inc。创建了新颖的ETS家族抑制剂 TK216。（RHA）导致转录变化和凋亡。复发或难治性ES，这是一种罕见的小儿癌，历史上对信任有效，非常具有挑战性，在1期临床试验中。可管理的骨髓抑制作用，没有明显的剂量。方案表现出早期的令人兴奋的证据表明1种手术完整患者的活性反应（CR）和1个很好的部分反应（PR； 90％的肿瘤收缩）。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/耐火ES是由EWS-ETS融合蛋白驱动的染色体易位。 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，通过破坏或促进蛋白 - 蛋白质相互作用（PPI）来靶向EWS-ET。对于针对EWSET的靶向疗法，临床开发正在加速TK216作为通过门诊泵连续14天，这使ES患者可以进入并提供功效证明。癌症几乎没有或没有其他治疗方案，它给ES带来了明显的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 - 因此，我们提出了两个基于TK216的建议的主要目标疗法：a）TK216的活性频谱对ETS转录因子的成员的删除家庭和b）开发TK216的口服剂量形式，包括GLP药理学/毒理学研究和 GMP制造业。允许将TK216研究扩展到其他肿瘤学指示中。是为了开发口头配方并获得研究支持研究的临床前数据新毒品（IND）的指示扩展应用程序。