Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China; Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China.
Bioorg Med Chem. 2020 Aug 15;28(16):115584. doi: 10.1016/j.bmc.2020.115584. Epub 2020 Jun 15.
Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it's necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists.
三阴性乳腺癌（TNBC）是乳腺癌的一个亚型，其生存率低于其他乳腺癌类型。最近的研究表明，异常的 Hedgehog（Hh）途径在 TNBC 中被激活，这些治疗耐药的癌症对 Hh 途径的抑制敏感。Smoothened（Smo）蛋白是 Hh 信号传导的重要组成部分，也是有吸引力的药物靶点。Vismodegib（VIS）是研究最广泛的 Smo 抑制剂之一。但是，Smo 抑制剂的临床应用仅限于患有基底细胞癌和急性髓细胞白血病的成年患者，且具有许多副作用。因此，有必要开发具有更好特性的新型 Smo 抑制剂。设计、合成并筛选了 20 个 [1,2,4]三唑并[4,3-a]吡啶作为 Smo 抑制剂。其中四个新型化合物直接与 Smo 蛋白结合，结合亲和力强于 VIS。新化合物在体外对癌细胞系表现出广泛的抗增殖活性，尤其是三阴性乳腺癌细胞。机制研究表明，TPB15 可显著诱导 MDA-MB-468 细胞的细胞周期停滞和凋亡。TPB15 阻断 Smo 向纤毛的易位，并降低 Smo 蛋白和 mRNA 表达。此外，下游调节因子Gli 癌基因 1（Gli1）的表达明显受到抑制。最后，TPB15 在我们的动物模型中比 VIS 具有更低的毒性，表现出更强的抗肿瘤活性。因此，这些结果支持进一步优化这种新型支架以开发改进的 Smo 拮抗剂。
