Khatra Harleen, Bose Chandra, Sinha Surajit
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032. India.
Curr Med Chem. 2017;24(19):2033-2058. doi: 10.2174/0929867324666170316115500.
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.
A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented.
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.
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.
进化上保守的刺猬信号通路（Hh）是许多后生动物胚胎发育的关键调节因子之一。由于该信号通路失调会导致各种恶性肿瘤和发育障碍，因此小分子抑制剂已广泛针对该通路展开研究。因此，阻断该通路可能成为治疗刺猬信号通路依赖性癌症的新治疗途径。本文综述了脊椎动物细胞中刺猬信号通路的机制，概述了已报道的小分子Hh信号通路抑制剂，并简要讨论了其中一些抑制剂的合成路线和构效关系研究。
对迄今为止报道的与合成和天然存在的Hh信号拮抗剂相关的文献进行全面综述。
鉴于与激酶、微管蛋白或组蛋白去乙酰化酶抑制剂相比，小分子靶向该信号通路用于癌症治疗具有选择性，已经发现了几种这样的拮抗剂，其中一些正处于临床前开发和临床研究阶段。大多数已报道的小分子主要拮抗平滑受体，尽管也发现了靶向Gli1转录因子和Shh配体的药物。迄今为止，已有9种Smo拮抗剂进入临床试验。GDC-0449/维莫德吉和NVP-LDE225/厄立莫德吉已获美国食品药品监督管理局（FDA）批准用于治疗基底细胞癌。
面临的挑战是识别靶向Smo下游信号通路的药物，并深入了解耐药机制，从而制定克服对当前Smo抑制剂获得性耐药的策略。
