Development of hedgehog pathway inhibitors by epigenetically targeting GLI through BET bromodomain for the treatment of medulloblastoma

• 作者: Xiaohua Liu Yu Zhang Yalei Li Juan Wang Huaqian Ding Wenjing Huang Chunyong Ding Hongchun Liu Wenfu Tan Ao Zhang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Original articles
• 页码范围: 488-504
• 页数: 17页
• 语种: 英文

摘要

Medulloblastoma(MB)is a common yet highly heterogeneous childhood malignant brain tu-mor,however,clinically effective molecular targeted therapy is lacking.Modulation of hedgehog(HH)signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4(BRD4)has recently spurred new interest as potential treatment of HH-driven MB.Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated onco-gene homolog(GLI)protein,the BRD4 inhibitor 2 was selected as the lead for further structural optimi-zation,which led to the identification of compounds 25 and 35 as the high potency HH inhibitors.Mechanism profiling showed that both compounds suppressed HH signaling by interacting with the tran-scriptional factor GLI,and were equally potent against the clinical resistant mutants and the wild type of smoothened(SMO)receptor with IC50 values around 1 nmol/L.In the resistant MB allograft mice,com-pound 25 was well tolerated and markedly suppressed tumor growth at both 5 mg/kg(TGI = 83.3％)and 10 mg/kg(TGI = 87.6％)doses.Although further modification is needed to improve the pharmacokinetic(PK)parameters,compound 25 represents an efficacious lead compound of GLI inhibitors,possessing optimal safety and tolerance to fight against HH-driven MB.