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作为一种针对NTRK融合瘤的新型第二代抑制剂的BPI-28592

Jin Sheng¹, Hong Chen², Bang Fu²

¹Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

NPJ precision oncology

|September 10, 2024

概括

一种新的药物,BPI-28592,有效地向神经营性热胺受体激酶 (NTRK) 融合癌症,即使是那些具有耐药突变的癌症. 这种第二代抑制剂在克服对TRK抑制剂的获得性耐药性方面表现有前途.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

异常激活热氨酸受体激酶 (TRKs) 驱动神经营性热氨酸受体激酶 (NTRK) 融合癌症.
获得的耐药性突变限制了第一代TRK抑制剂的疗效.
开发新的抑制剂对于治疗耐性NTRK融合癌症至关重要.

研究的目的:

推出BPI-28592,一种新型的第二代TRK抑制剂.
评估BPI-28592对TRK融合阳性癌症的疗效,包括具有耐药突变的癌症.
评估BPI-28592在克服药物耐药性的潜力.

主要方法:

对接模拟用于预测药物向相互作用.
生物化学分析以确定对TRKA,TRKB和TRKC的抑制和选择性.
在体外研究评估细胞增殖和TRK信号.
在TRK融合轴承模型中进行体内异种移植研究.
在患有NTRK3融合阳性黑色素瘤的患者中进行临床评估.

主要成果:

对接模拟表明,BPI-28592与TRK突变没有固体障碍.
BPI-28592对TRKA,TRKB和TRKC表现出强大的抑制和高选择性.
该抑制剂显著降低了癌细胞的增殖,并阻断了TRK信号通路.
在临床前的异种移植模型中,BPI-28592有效抑制了瘤生长.
在患有恶性黑色素瘤的患者中观察到完整的反应,该患者患有AP3S2-NTRK3融合.

结论:

BPI-28592是一种有前途的第二代TRK抑制剂,对TRK融合阳性癌症具有广泛的疗效.
它的设计表明,它有可能克服TRK抑制剂中获得的耐药性突变.
临床数据支持BPI-28592在治疗NTRK融合驱动的恶性瘤中的治疗潜力.

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