Deng Fang-Bo, Jia Hong-Wei, Hu De-Xiang, Li Zhen-Li, Xiu Xiao-Meng, Zhao Xue-Qi, Liu Yang, Yang Hua-Li, Cheng Maosheng
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University Shenyang 110016 PR China.
RSC Med Chem. 2025 May 21. doi: 10.1039/d5md00007f.
The development of multi-target inhibitors has garnered considerable attention in the field of cancer therapy. We have designed and synthesized a total of 80 derivatives, categorized into , , and series. Among these compounds, C12 (IMPDH II, IC = 84.69 ± 0.83 nM; HDAC1, IC = 81.75 ± 0.82 nM) and C18 (IMPDH II, IC = 820.50 ± 1.41 nM; HDAC1, IC = 131.90 ± 1.02 nM) exhibited promising inhibitory activity against IMPDH II and HDAC1. Compared to the IMPDH-positive compound MPA (IC = 403.23 ± 2.92 nM) and the HDAC-positive compound SAHA (IC = 1165.72 ± 1.22 nM), compound C12 (IC value of 305.31 ± 0.67 nM) demonstrated superior anti-proliferative activity against K-562 cells . Compound C12 exhibited good liver microsomal stability with a moderate half-life ( ). Furthermore, compound C12 exhibited acceptable pharmacokinetics of properties. In conclusion, compound C12 represents a potential new dual inhibitor targeting both IMPDH II and HDAC1.
多靶点抑制剂的研发在癌症治疗领域已引起了相当大的关注。我们总共设计并合成了80种衍生物，分为 、 和 系列。在这些化合物中，C12（IMPDH II，IC = 84.69 ± 0.83 nM；HDAC1，IC = 81.75 ± 0.82 nM）和C18（IMPDH II，IC = 820.50 ± 1.41 nM；HDAC1，IC = 131.90 ± 1.02 nM）对IMPDH II和HDAC1表现出有前景的抑制活性。与IMPDH阳性化合物MPA（IC = 403.23 ± 2.92 nM）和HDAC阳性化合物SAHA（IC = 1165.72 ± 1.22 nM）相比，化合物C12（IC值为305.31 ± 0.67 nM）对K-562细胞表现出更强的抗增殖活性 。化合物C12表现出良好的肝微粒体稳定性，半衰期适中（ ）。此外，化合物C12表现出可接受的药代动力学性质。总之，化合物C12代表了一种潜在的新型双靶点抑制剂，可同时靶向IMPDH II和HDAC1。
