Design,Synthesis And Antitumor Activity Of Novel Polo-like Kinase 1 Selective Inhibitors Having The Tetrahydropteridin Scaffold

The family of Polo-like kinases?Plks?has five members,Plk1-5,which are serine/threonine kinases of the cell cycle in mammalian cells.Plk1 is a validated target for the treatment of cancer.In recent years,small-molecule Plk1 inhibitors developed by researchers,such as BI 2536 and BI 6727,have shown good medicinal effects in clinical trials,but they still have some problems,such as drug resistance,poor therapeutic effects of single drug,and so on.Therefore,developing potent selective Plk1 inhibitors with satisfactory solubility is extremely desired in this field.In this dissertation,by taking advantage of residue differences among the ATP-binding pockets of Plk1,Plk2 and Plk3,and employing a SBDD strategy and using BI 2536 and BI 6727 as the template compounds,we designed and synthesized a series of Plk1 inhibitors having the tetrahydropteridin scaffold.All compounds were evaluated for inhibiting Plk1 and family selectivity.The results showed that most of target compounds exhibited better inhibitory activity and selectivity than BI 2536.Compound L34 stood out from the compounds reported herein.It received an IC₅₀value of 3.89 n M against Plk1 and good selectivity to Plk2?selectivity index 7.84?and Plk3?selectivity index 5.69?,significantly surpassing BI 2536.In the MTT assay,our compounds showed nanomolar inhibitory activity against several cancer cell lines.Among them,L34 exhibited better antiproliferative activity in nine cancer cell lines than BI 2536,especially in K562 and Hela cells with GI₅₀ values of 10.6 n M and 8.03n M,respectively,nearly 6 times and 4 times higher than BI 2536.L34 also showed significantly improved solubility.In summary,a series of tetrahydropteridin derivatives as potent selective Plk1 inihibotrs were obtained,laying the foundation for the development of better targeted anticancer drugs.