While splice modulators have entered clinical trials, limited clinical efficacy in splicing factor mutation-driven malignancies, such as acute myeloid leukemia, has remained a challenge. There is a pressing unmet medical need for developing potent small molecule splice modulators for the treatment of a broad array of malignancies characterized by splicing deregulation. However, the inability to practically access gram-scale lead molecules with viable pharmacological properties continues to hinder their application. Here, we report a scalable approach to prepare 17S-FD-895, a potent in vivo active splice modulator. The strategy described herein not only provides material to enable clinical translation but also furthers lead validation by expanding the structure-activity relationships that guide splice modulation.

尽管剪接调节剂已经进入临床试验，但是在剪接因子突变驱动的恶性肿瘤例如急性髓细胞白血病中有限的临床疗效仍然是一个挑战。迫切未满足的医学需求，即开发有效的小分子剪接调节剂，以治疗以剪接失调为特征的各种恶性肿瘤。然而，无法实际获得具有可行药理学特性的克级铅分子继续阻碍其应用。在这里，我们报告了一种可扩展的方法来制备17 S -FD-895（一种有效的体内有源拼接调制器。本文描述的策略不仅提供了能够进行临床翻译的材料，而且还通过扩展指导剪接调控的结构-活性关系进一步促进了前导验证。