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发现ZN-c5,一个口服生物可用的选择性雌激素受体降解剂 (SERD),具有改善的药理动力学

Sayee G Hegde¹, Peter Q Huang¹, Kevin D Bunker¹

¹Zentalis Pharmaceuticals, San Diego, California 92121, United States.

Journal of medicinal chemistry

|July 14, 2025

概括

研究人员开发了一种优化的口服选择性雌激素受体降解剂 (SERD),使用双循环[1.1.1]坦 (BCP) 环. 这种新型SERD,化合物4 (ZN-c5),在早期临床试验中表现出强大的疗效和有利的药理动力学.

科学领域:

药用化学医学化学
药理学药理学是指药理学的学科.
药物发现药物发现药物发现

背景情况:

选择性雌激素受体降解剂 (SERD) 在雌激素受体阳性乳腺癌的内分泌治疗中至关重要.
双环[1.1.1]坦 (BCP) 环系统在药物设计中提供作为环和基组替代物的潜在优势.
对于含有BCP的化合物,临床数据有限,需要进一步调查.

研究的目的:

设计和优化一个口服选择性雌激素受体降解剂 (SERD) 结合了bicyclo[1.1.1]pentane (BCP) 支架.
评估优化SERD的体外和体外药理动力学和药理动力学特性.
在1/2期试验中评估化合物的临床安全性和疗效.

主要方法:

基于结构的药物设计和化学合成,以整合BCP环系统.
在体外测试以确定细胞功效和ADME (吸收,分布,新陈代谢,分泌) 属性.
在动物和非动物物种中的体内药理动力学研究.
1/2期临床试验,以评估人类的药理动力学和安全性.

主要成果:

含有BCP环的化合物4 (ZN-c5) 对抗乳腺癌系的细胞有很好的功效.
该化合物在体外表现出有利的ADME特性,并在临床前物种体内暴露高.
1/2期临床试验表明,在每日50毫克剂量时,人体暴露很高.

结论:

BCP环系统是开发强效和口服生物可用SERDs的可行支架.
化合物4 (ZN-c5) 在乳腺癌治疗中显示出有前途的临床开发特征.
成功进入临床试验验证了ZN-c5.5的设计策略和潜力.

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