Design,Synthesis And Activity Study Of A Novel PI3K Degradation Based On PROTAC Technology

PI3K kinase is a signal transduction enzyme in the cell,which plays an important regulatory role in key cell processes such as cell growth,proliferation,differentiation,and movement.The PI3 K signal pathway is a central signal transduction pathway involved in many basic cell functions.Dysregulation of this pathway has been detected in the occurrence of many diseases.Therefore,the research on the new type of highefficiency and low-toxicity PI3 K kinase inhibitors has always been the key to the design of anti-tumor drugs.Proteolysis targeting chimera(PROTAC)is a new technology that uses the ubiquitinproteasome system to degrade targeted protein.PROTAC can not only solve the common problems such as drug resistance and off-target effects,but also provide new technologies for basic biological research.There are only a few applications of PROTAC on PI3 K kinase.Using PROTAC,the targeted degradation of PI3 K kinase affects many cellular processes and provides a new way for the treatment of malignant tumors.In the previous work,we obtained a highly effective PI3K/m TOR inhibitor——15a with anti-tumor effect.This project aims to design and synthesize small molecule degradation agents that PI3 K kinase targeted on PROTAC.We first modified the structure of the 15 a compound and obtained several PI3 K kinase inhibitors.According to the PROTAC molecular design principle,we selected different linker to link the PI3 K inhibitor with the VHL E3 ligase ligand,and obtained a series of small molecules that target the degradation of PI3 K kinase by recruiting VHL E3 streptokinase.This is a new research of PROTAC on PI3 K kinase.In our project,two compounds were discovered and obtained that have obvious degradation effects on PI3 K kinase.The most representative one is HL-9,which have significant degradation effects on PI3 K kinase at a concentration of 10μM within 8hours.This provides theoretical support for the application of PROTAC on PI3 K kinase.In addition,the series of compounds we have obtained have a very significant effect on class Ⅲ PI3 K kinase.The class Ⅲ PI3 K kinase can be efficiently degraded at a concentration of 10 μM.It provides a new strategy for exploring the basic biological functions of type Ⅲ PI3 K kinase,which is currently less studied.In short,as a new type of PI3K degrading agent,this series of compounds showed good activity at the cell and kinase level,laying a foundation for further research on targeting PI3 K kinase.At the same time,the acquisition of this series of compounds not only provides ideas for the anti-tumor research of the PI3 K signaling pathway,but also provides strong practical support for the PROTAC technology.