化学
铈替尼
碱性抑制剂
阿列克替尼
药理学
间变性淋巴瘤激酶
药物发现
癌症研究
融合蛋白
药品
基因
生物化学
重组DNA
内科学
恶性胸腔积液
医学
胸腔积液
作者
Haoxuan Zhou,Mingxing Hu,Hui Jie,Yujue Li,Kexin Tang,Lili Pan,Chengyali Liu,Бо Лю,Hao Chen,Yuanwei Chen,Yi Luo,Youling Gong,Yongmei Xie
标识
DOI:10.1016/j.ejmech.2024.116827
摘要
Anaplastic lymphoma kinase (ALK) fusion genes promote a variety of human malignancies. Although several ALK inhibitors have significantly improved disease prognosis in patients with ALK positive cancers, the persistent emergence of acquired drug-resistant mutations remain the major problem in clinic treatment. Adoption of new therapeutic strategies such as proteolysis targeting chimera (PROTAC) to overcome drug resistance in BTK/AR-related cancers have shown promising prospect. Herein, we reported the integrate ALK PROTACs through overall optimization of linker, revealed that subtle structural differences can lead to significant activity difference, indicating the key role of conformation of PROTACs in inducing the formation of E3-PROTAC-target protein ternary complexes. A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. 4B effectively induced long lasting degradation of ALK fusion proteins and strong repression of downstream pathway in Karpas 299 cells (DC
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