Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma
Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma
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DOI：
10.18632/oncotarget.1495
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发表时间：
2014-01-01
期刊：
影响因子：
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通讯作者：
Toretsky, Jeffrey A.
中科院分区：
文献类型：
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作者：
Hong, Sung-Hyeok;Youbi, Sarah. E.;Toretsky, Jeffrey A.
转录因子长期以来被认为是治疗的“无药可救”目标。对蛋白质生物化学的增强识别以及对具有更有针对性的方法来治疗癌症的需求使得转录因子可用于治疗开发。由于转录因子缺乏酶结构域，因此这些蛋白质的特异性靶向具有独特的挑战。一个挑战是影响小分子获得阻断蛋白质相互作用的疏水微环境。靶向的最有吸引力的转录因子是由肿瘤特异性染色体易位形成的那些，其是经验证的致癌驱动蛋白。EWS-FLI 1是尤文肉瘤（ES）特异性易位的融合蛋白。我们过去的工作创造了小分子YK-4-279，它阻止EWS-FLI 1与RNA解旋酶A（RHA）相互作用。为了通过创造临床上有用的药物来实现该领域的长期承诺，需要允许体内施用的步骤。这些研究确定了小分子蛋白质-蛋白质抑制剂持续存在数天的需要。我们描述了YK-4-279及其单个对映体的药代动力学。体内研究证实了先前的体外实验，显示（S）-YK-4-279为EWS-FLI 1特异性对映异构体，表明诱导细胞凋亡和减少EWS-FLI 1调节的小窝蛋白-1。我们已经建立了ES的第一个大鼠异种移植模型，基于PK建模用（S）-YK-4-279给药治疗，导致6个ES肿瘤中的2个持续完全反应。结合实验室研究，药代动力学测量和建模，使我们能够创建一个范例，可以使用体外数据和药代动力学模拟优化体内系统。因此，（S）-YK-4-279作为一种小分子药物准备继续开发，以进行首次人体临床试验。
Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial.