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Strategies to target the Hedgehog signaling pathway for cancer therapy
Medicinal Research Reviews ( IF 13.3 ) Pub Date : 2018-01-05 , DOI: 10.1002/med.21482
Minhang Xin 1, 2 , Xinyue Ji 2 , Ladie Kimberly De La Cruz 2 , Suresh Thareja 2 , Binghe Wang 2
Affiliation  

Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first‐in‐class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

中文翻译:

针对刺猬信号通路进行癌症治疗的策略

刺猬(Hh)信号是人体中必不可少的途径,并且在胚胎发育和组织模式中起主要作用。通过偶发突变或其他机制对Hh信号通路的组成性激活与各种实体恶性肿瘤中的癌症发展和进展显着相关。因此,针对Hh信号通路的靶向抑制已成为一种有吸引力且经过验证的治疗策略,可用于治疗多种癌症。Vismodegib是首个Hh信号通路抑制剂,于2012年获得美国食品和药物管理局的批准,另一种有效的Hh通路抑制剂Sonidegib于2015年获得FDA的批准,作为一种局部晚期或转移性基底细胞癌的新疗法。vismodegib和sonidegib的临床成功通过靶向平滑的(Smo)受体为Hh信号通路抑制剂的开发提供了有力的支持。此外,基于对其他治疗益处的鉴定,还已经寻求了针对Smo下游或上游蛋白质的Hh信号通路抑制剂。近来,在Hh单一化和该途径的抑制剂方面已经取得了很大的进展。在此,对药物化学策略,尤其是不同种类的Hh抑制剂的结构优化过程进行了全面总结。还讨论了进一步的治疗潜力和挑战。在确定其他治疗益处的基础上,还追求了Smo下游或上游的药物。近来,在Hh单一化和该途径的抑制剂方面已经取得了很大的进展。在此,对药物化学策略,尤其是不同种类的Hh抑制剂的结构优化过程进行了全面总结。还讨论了进一步的治疗潜力和挑战。在确定其他治疗益处的基础上,还追求了Smo下游或上游的药物。近来,在Hh单一化和该途径的抑制剂方面已经取得了很大的进展。在此,对药物化学策略,尤其是不同种类的Hh抑制剂的结构优化过程进行了全面总结。还讨论了进一步的治疗潜力和挑战。
更新日期:2018-01-05
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