使用DNA编码化学技术发现高强度和ALK2/ALK1选择性激酶抑制剂
Ravikumar Jimmidi1,2, Diana Monsivais1,2, Hai Minh Ta1,2
1Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030.
概括
研究人员使用DNA编码化学方法开发出强大的ALK2抑制剂. 这些化合物,包括CDD-2789,通过阻断ALK2信号传递,显示出治疗纤维发育不良症和癌症的前景.
科学领域:
- 生物化学 生物化学
- 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:
- 活性蛋白受体1型 (ACVR1;ALK2) 和ACVRL1 (ALK1) 是TGF-β家族受体,对BMP和活性蛋白信号传递至关重要.
- 激活ALK2的突变与骨性纤维化成形进展 (FOP) 和各种癌症有关,包括质瘤,表皮瘤,子宫内膜瘤,黑色素瘤,肺癌和结直肠癌.
- 在胰腺癌中观察到高ALK2表达,突出显示了其致癌潜力.
研究的目的:
- 用DNA编码化学方法识别ALK2激酶域的强效和选择性抑制剂.
- 描述新型ALK2抑制剂的药理特征和作用机制.
- 评估ALK2抑制在FOP细胞模型中的治疗潜力.
主要方法:
- 从DNA编码化学库 (DECL) 选3940亿种化合物,对抗ALK2激酶域.
- 脱DNA合成,生物化学验证,以及对DECL的结构-活性关系研究.
- 激酶查 (KINOMEscan),纳米BRET测定和使用FOP患者纤维细胞的基于细胞的研究.
主要成果:
- 识别具有良好的代谢稳定性和药理学特征的纳米强度ALK2抑制剂,包括CDD-2789.
- 晶体结构显示了通过范德瓦尔斯相互作用和键与ALK2活性位点结合的抑制剂.
- CDD-2789对ALK2/ALK1具有很高的选择性,并且在FOP纤维细胞中有效减弱了BMP/活性因子诱导的SMAD1/5酸化.
结论:
- CDD-2789是一种强效和选择性的ALK2抑制剂,具有潜在的治疗应用.
- 开发的抑制剂作为研究ALK2/ALK1生物学的有价值的工具化合物.
- 向抑制ALK2代表了治疗FOP和某些癌症的有希望的策略.
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