发现一种选择性,口服可生物利用的RET降解剂,在各种突变中具有有效性
Mo Hualong1, JieYing Liu1, Ting Yin1
1School of Pharmacy and Food Engineering, Wuyi University, Jiangmen 529020, China.
Journal of medicinal chemistry
|January 8, 2025
概括
一种新型药物RD-23有效向癌症中的RET突变. 这种针对蛋白质分解的嵌合体 (PROTAC) 显示了RET蛋白的强烈抑制和降解,为RET驱动的癌症提供了有前途的新疗法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 在转移过程中重新排列的 (RET) 突变,如G810C,限制了当前RET抑制剂在RET驱动癌症中的有效性.
- 开发新的治疗策略对于克服抵抗机制和改善治疗结果至关重要.
研究的目的:
- 设计和评估新型RET蛋白解向仿真体 (PROTACs),以克服RET抑制剂耐药性.
- 确定一种强大且有选择性的RET PROTAC,能够降解突变的RET蛋白.
主要方法:
- 在selpercatinib (LOXO-292) 支架的基础上设计和合成了RET PROTAC.
- 在基于细胞的测定中评估了抗增殖活性和RET蛋白降解.
- 在异种移植小鼠模型中评估了口服生物可用性和体内疗效.
主要成果:
- 确定RD-23是一种强效和选择性的RET PROTAC,具有针对各种RET突变的纳米IC50值.
- RD-23选择性诱导RETG810C突变通过全方位蛋白酶系统 (DC50 = 11.7 nM) 的降解.
- 与LOXO-292相比,RD-23在体内显示出口服生物可用性和优越的抗瘤疗效.
结论:
- RD-23是一种强大的RET PROTAC,可以有效降解突变的RET蛋白,包括G810C变种.
- RD-23对治疗RET驱动的癌症,包括对常规抑制剂耐药的癌症,具有有前途的治疗潜力.
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