Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (4), p.1224-1228
• Main Authors: Fan, Yin-Bo, Li, Kun, Huang, Min, Cao, Yu, Li, Ying, Jin, Shu-Yu, Liu, Wen-Bing, Wen, Jia-Chen, Liu, Dan, Zhao, Lin-Xiang
• Format: Article
• Language: English
• Subjects: Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Binding Sites; Cell Line, Tumor; Cell Survival - drug effects; Drug Design; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Pim-1 kinase inhibitors; Prostate cancer cells; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - metabolism; Pyrido[3,2-d]-1,2,3-triazines; Triazines - chemistry; Triazines - metabolism; Triazines - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.032

[Display omitted] A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prostate cancer cells. Among them, 6b, 6h and 6m showed the best Pim-1 inhibitory activity with IC50 values of 0.69, 0.60 and 0.80μM, respectively. Furthermore, compounds 6b, 6i, 6j and 6m showed strong inhibitory activity to human prostate cancer LNcap and PC-3 cell lines with IC50 values at low micromolar level. Structure–activity relationship analysis revealed that appropriate substitutions at C-6 positions contributed to the kinase inhibition and antiproliferative effects. Moreover, western blot assay suggested that 6j could decrease the levels of p-BAD and p-4E-BP1 in a dose-dependent manner in PC-3 cells. Docking studies showed that 3-N of the scaffold formed a hydrogen bond with Lys67, aromatic 4-aniline formed a key π–π stack with Phe49. Taken together, this study might provide the first sight for developing the pyrido[3,2-d]-1,2,3-triazine scaffold as novel Pim-1 inhibitors.