文章：

理解激活环突变在FLT3-ITD药物疗效中的作用

Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD

原文发布日期：15 November 2023

DOI: 10.3390/cancers15225426

类型: Article

开放获取: 是

英文摘要：

The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction with tyrosine kinase inhibitors. Coupled with this, the research leverages molecular contrastive learning and protein language modeling to examine interactions between small molecule inhibitors and FLT3 activation loop mutants. Utilizing the ConPLex platform, over 5.7 million unique FLT3 activation loop mutants—small molecule pairs were analyzed. The binding free energies of three inhibitors were assessed, and cellular apoptotic responses were evaluated under drug treatments. Notably, the introduction of the Xepto50 scoring system provides a nuanced metric for drug efficacy. The findings underscore the modulation of molecular interactions and cellular responses by Y842 mutations in FLT3-KD, highlighting the need for tailored therapeutic approaches in FLT3-ITD-related malignancies.

摘要翻译： 

III型受体酪氨酸激酶FLT3是造血祖细胞调控的关键激酶，其内部串联重复（ITD）等突变在急性髓系白血病（AML）中具有重要病理意义。本研究深入探讨了FLT3的结构复杂性、激活环突变体的功能及其与酪氨酸激酶抑制剂的相互作用。同时，研究结合分子对比学习和蛋白质语言模型，系统分析了小分子抑制剂与FLT3激活环突变体间的相互作用。通过ConPLex平台，对超过570万个独特的FLT3激活环突变体-小分子配对进行了分析。评估了三种抑制剂的结合自由能，并在药物治疗条件下检测了细胞凋亡反应。值得注意的是，Xepto50评分系统的引入为药物疗效提供了精细化评估指标。研究结果揭示了FLT3激酶结构域中Y842突变对分子相互作用及细胞应答的调控作用，强调了针对FLT3-ITD相关恶性肿瘤制定个体化治疗策略的必要性。

原文链接：

Understanding the Role of Activation Loop Mutants in Drug Efficacy for FLT3-ITD