Abstract：
PAK4 has been validated as a crucial effector of various signal pathways and play an important role in driving tumor progression. Here, we developed a series of 7H-pyrrolo [2,3-d] pyrimidine derivatives as PAK4 inhibitors. Compounds 5n and 5o showed higher enzymatic inhibitory activities (IC50 = 2.7 and 20.2 nM, respectively) and potent activity (IC50 = 7.8 and 38.3 nM, respectively) against MV4-11 cell line. Further flow cytometry assay revealed that the compound 5n can arrest MV4-11 cells at G0/G1 phase and induce cell apoptosis. Molecular mechanism study indicated that compound 5n regulated the phosphorylation of PAK4 in vitro. The docking study supported that compound 5n binds to PAK4 through various hydrogen bonding interactions and hydrophobic interactions. Thus, compound 5n represents a promising lead for the discovery of PAK4 directed therapeutic agents and may be considered for further drug development.
摘要：
PAK4已被验证为各种信号通路的关键效应子，并在驱动肿瘤进展中发挥重要作用。这里,我们开发了一系列7H-吡咯并[2,3-d]嘧啶衍生物作为PAK4抑制剂。化合物5n和5o显示出较高的酶抑制活性(IC50=2.7和20.2nM,分别）和有效活性（IC50=7.8和38.3nM，分别）针对MV4-11细胞系。进一步的流式细胞术分析显示,化合物5n可以将MV4-11细胞阻滞在G0/G1期并诱导细胞凋亡。分子机制研究表明，化合物5n在体外调节PAK4的磷酸化。对接研究支持化合物5n通过各种氢键相互作用和疏水相互作用与PAK4结合。因此，化合物5n代表了发现针对PAK4的治疗剂的有希望的线索，并且可以考虑用于进一步的药物开发。
