Abstract:
The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.
摘要:
Hedgehog(Hh)信号通路在多种生理功能中起重要作用。几种恶性肿瘤,如基底细胞癌(BCC)和髓母细胞瘤(MB),已与Hh信号的异常激活有关。尽管已经开发了治疗药物来抑制Hh途径依赖性癌症的生长,耐药性仍然是癌症治疗的主要障碍。这里,我们展示了新发现的,2-{3-[1-(苄基磺酰基)-1,2,3,6-四氢吡啶-4-基]-2-甲基-1H-吲哚-1-基}-1-(吡咯烷-1-基)乙烯酮类似物(LKD1214)在抑制Hh途径激活方面表现出与维莫德吉相当的效力。LKD1214通过阻断纤毛易位来抑制平滑(SMO)活性。有趣的是,我们还发现,与其他SMO调节化学品相比,它与SMO具有独特的结合界面。值得注意的是,它保持对SmoD477H突变体的抑制活性,如在对维莫德吉布耐药的BCC患者中观察到的。此外,LKD1214抑制MB小鼠模型中的肿瘤生长。总的来说,这些研究结果表明,LKD1214具有克服Hh依赖性癌症耐药的治疗潜力.