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发现RP-1664:一类中的第一口服生物可用,选择性PLK4抑制剂

Frédéric Vallée¹, Matias Casás-Selves¹, Monica Bubenik¹

¹Repare Therapeutics, Inc., 7210 Frederick-Banting, Ville St-Laurent, QC H4S 2A1, Canada.

Journal of medicinal chemistry

|May 16, 2025

概括

研究人员开发了RP-1664,一种强大的Polo类激酶4 (PLK4) 抑制剂,用于使用TRIM37基因放大来治疗癌症. 这种候选药物显示了改善的特性,现在正在第一阶段的临床试验中.

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:

波罗样类激酶4 (PLK4) 对于中心球生物生成至关重要,并且在癌症中通过TRIM37基因放大具有合成致命性.
以前的PLK4抑制剂在选择性和药理动力学特性方面面临着挑战.
已知抑制剂Centrinone B表现出代谢不稳定性和口服生物可用性较差.

研究的目的:

开发一种具有强大和选择性的PLK4抑制剂,具有改进的类似药物的特性.
确定用于TRIM37增强癌症的新型治疗剂.

主要方法:

基于结构的药物设计 (SBDD) 用于优化Centrinone B.
进行了基因组分析,以评估对相关基因酶的选择性.
临床前研究评估了RP-1664在异种移植模型中的药理动力学,药理动力学和疗效.

主要成果:

与之前的抑制剂相比,RP-1664显示出强度,选择性和ADME特性显著改善.
在AURKA/B和PLK1基因酶上观察到精致的选择性.
RP-1664有效地扰乱了中心生物发生,在体内显示了目标参与,并在TRIM37增强异种移植模型中证明了有效性.

结论:

RP-1664 是一流的临床候选者,针对PLK4用于TRIM37增强癌症.
优化的抑制剂表现出有利的药理动力学和强大的抗瘤活性.
目前RP-1664正在进行高级固体瘤的第一阶段临床试验.

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