Design,Synthesis And Activity Screening Of PD-1/PD-L1 Small Molecule Inhibitors

From the perspective of immunomodulation,the occurrence and development of tumors are the result of their immune mechanisms being suppressed and and unable to normally resist the invasion of tumor cells.Cancer immunotherapy has become the most promising research area in the current field of cancer therapy.Among them,PD-1/PD-L1 immune checkpoint inhibitors have developed rapidly and are relatively mature.At present,six drugs have been approved for marketing.In this paper,based on the structure of biphenyl small molecule PD-1/PD-L1 small molecule inhibitors,referring to relevant literature reports,the pharmacophore model of PD-1/PD-L1 inhibitors was analyzed and summarized.Using the closed-loop principle and bioisosterism,respectively,two series of target compounds were designed:a series of biphenyl small molecule compounds containing pyrimidine structure and a series of biphenyl small molecule compound containing triazine structure.Through the inverse synthesis analysis of the structure of the two series of comp ounds,the synthesis route was determined,and 36 target compounds were finally syn thesized,the structure of which was confirmed by HRMS and ~1H-NMR.Using HTRF assay and BMS-37 as a positive control drug,two synthetic compounds were screened for in vitro PD-1/PD-L1 inhibitory activity,and the results indicated that most of the compounds showed certain inhibitory activity at 1?M,verified the feasibility of structural design ideas.Among them,the compound HK-3and HK-13 dispiayed the most promsing inhibitory activity with the inhibition rate of69.76%and 63.83%.In addition,based on the results of the inhibitory activity,the structure-activity relationships of the two series of compounds were further analyzed and summarized.Finally,in order to guide the further structural optimization,using the Autodock software,molecular docking simulations of HK-3 and HK-13 were performed to clarify the binding model and interaction of HK-3 and HK-13 with PD-L1 protein,respectively.