摘要
背景:在进化上保守的Hedgehog(HH)信号通路之一是许多后生动物胚胎发育的关键因子。这条途径被小摩尔广泛地瞄准。分子抑制剂为失调导致各种恶性肿瘤和发育障碍。因此,阻断这种通路可能是治疗刺猬依赖C的一种新的治疗途径。ancers。本文综述了Hedgehog信号在脊椎动物细胞中的作用机制,概述了小分子HH通路抑制剂的合成路线和研究进展。其中一些简要讨论。 方法:综合报道了与合成和自然发生的HH信号拮抗剂有关的文献。 结果:由于靶向小分子的选择性,这一肿瘤治疗途径与激酶、微管蛋白或HDAC抑制剂相比,已经发现了一些这样的拮抗剂,其中S有些人是在临床前开发和临床研究。大多数报道的小分子拮抗剂主要是平滑的受体虽然靶向GLI1转录因子和嘘我-配体也被发现。到目前为止,九个SMO拮抗剂已在临床trials.gdc -评价0449 / vismodegib和nvp-lde225 / erismodegib,被授予由美国食品和药物管理局(FDA)批准了基底细胞癌的治疗。
关键词: Hedgehog通路,小分子,平滑,GLI,抑制剂,抗癌。
Current Medicinal Chemistry
Title:Discovery of Hedgehog Antagonists for Cancer Therapy
Volume: 24 Issue: 19
关键词: Hedgehog通路,小分子,平滑,GLI,抑制剂,抗癌。
摘要: Background: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly.
Methods: A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented. Results: Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Gli1 transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials.GDC- 0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma. Conclusion: The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.Export Options
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Cite this article as:
Discovery of Hedgehog Antagonists for Cancer Therapy, Current Medicinal Chemistry 2017; 24 (19) . https://dx.doi.org/10.2174/0929867324666170316115500
DOI https://dx.doi.org/10.2174/0929867324666170316115500 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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