发现了结构约束的ALK2抑制剂
Héctor González-Álvarez1,2, Deeba Ensan1,2, Tao Xin1
1Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
Journal of medicinal chemistry
|March 18, 2024
概括
研究人员开发了新型ALK2抑制剂,其强度和选择性得到改善,用于治疗扩散内在庞丁质瘤 (DIPG). 这些化合物对DIPG的未来治疗发展充满希望.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 在瘤学瘤学.
背景情况:
- 扩散内在庞丁质瘤 (DIPG) 仍然是一个毁灭性的儿科脑瘤,治疗选择有限.
- 几十年的研究已经在DIPG患者的治疗结果中取得了微小的改善.
- 针对异常信号通路,例如涉及ALK2的信号通路,是开发新癌症疗法的关键策略.
研究的目的:
- 设计,合成和评估基于M4K2009的脚手架修改的新型ALK2抑制剂.
- 探索硬化策略对抑制剂强度和选择性的影响.
- 确定用于治疗DIPG的潜在候选药物.
主要方法:
- 新型以太结合和氨基结合受约束ALK2抑制剂的合成.
- 对ALK2.2的抑制剂功能的体外评估.
- 对相关激酶的选择性评估,例如ALK5.5.
- 在体内初步的药理动力学研究,包括血脑屏障的透.
主要成果:
- 发现了ALK2.2的强有力的以太连接抑制剂 (M4K2308,M4K2281) 和氨基连接抑制剂 (M4K2304,M4K2306).
- 与参考化合物相比,对ALK2的优越功效的证明.
- M4K2304和M4K2306对ALK2比ALK5.5具有异常的选择性.
- 在受限制的支架中观察到有利的体内药理动力学特征,包括血脑屏障的透.
结论:
- 开发出了具有增强功效和选择性的新型受约束ALK2抑制剂.
- 这些化合物代表了DIPG治疗开发的有希望的新化学空间.
- 需要在正方形DIPG模型中进行进一步的优化和评估.
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