Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem. 2020 Mar 15;28(6):115354. doi: 10.1016/j.bmc.2020.115354. Epub 2020 Feb 5.
A series of anthranilamide derivatives were designed and synthesized as novel smoothened (SMO) inhibitors based on the SMO inhibitor taladegib (LY2940680), which can also inhibit the SMO-D473H mutant, via a ring-opening strategy. The phthalazine core in LY2940680 was replaced with anthranilamide, which retained the inhibitory activity towards the hedgehog (Hh) signaling pathway as evidenced by a dual luciferase reporter gene assay. Compound 12a displayed the best inhibitory activity against the Hh signaling pathway with IC value of 34.09 nM, and exhibited better proliferation inhibitory activity towards the Daoy cell line (IC = 0.48 μM) than LY2940680 (IC = 0.79 μM).
设计并合成了一系列邻苯二甲酰胺衍生物，作为新型 smoothened（SMO）抑制剂，基于 SMO 抑制剂 taladegib（LY2940680），通过开环策略，它也可以抑制 SMO-D473H 突变体。LY2940680 中的酞嗪核心被邻苯二甲酰胺取代，保留了对 hedgehog（Hh）信号通路的抑制活性，这一点通过双荧光素酶报告基因检测得到证实。化合物 12a 对 Hh 信号通路表现出最佳的抑制活性，IC 值为 34.09 nM，对 Daoy 细胞系的增殖抑制活性（IC = 0.48 μM）优于 LY2940680（IC = 0.79 μM）。
