强效增强的皮模拟VHL带有改善的口服生物可用性
Hao Wu1, Jeremy Murray2, Noriko Ishisoko3
1Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
Journal of medicinal chemistry
|May 29, 2024
概括
研究人员利用结构-活性关系研究和NanoBRET试验优化了VHL配体. 新的GNE7599连接体显示了10倍更高的结合活性和提高了针对蛋白质降解研究的口服生物可用性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药用化学 医学化学
背景情况:
- ·希佩尔-林道 (VHL) 蛋白质对于调节细胞对低氧反应至关重要.
- VHL配体是有针对性的蛋白质降解 (TPD) 策略的关键组成部分,包括双价降解剂.
- 提高VHL连接体的强度和药理动力学特性对于推进TPD疗法至关重要.
研究的目的:
- 通过全面的皮相对结构-活性关系 (SAR) 方法,优化现有的希佩尔-林道 (VHL) 连接体.
- 识别具有增强结合亲和力和改善药物样性质的新型VHL配体.
- 为VHL路径研究和TPD应用开发一个有价值的工具组合.
主要方法:
- 对型VHL连接体进行系统结构-活性关系 (SAR) 分析.
- 使用细胞NanoBRET目标参与测试来测量结合亲和力.
- 包含化学修改,包括1,2,3-二醇替代和形状约束.
主要成果:
- 鉴定了1,2,3-triazole组作为左侧胺键的优质替代品,增加了结合活性10倍.
- 开发具有皮科莫拉结合亲缘关系的高强度VHL配体.
- 通过构造性修改,通过口服生物可用性显著改善.
结论:
- 优化的VHL连接体GNE7599代表了VHL连接体开发的重大进步.
- GNE7599显示出高强度和有利的药理动力学特性,使其适合用于TPD研究.
- 这项工作为进一步研究VHL途径和向蛋白质降解的更广泛领域提供了有价值的工具化合物.
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