Design And Synthesis Of Small Molecule Compounds Targeting RNA Splicing Factors And Their Anti-tumor Effects

Human heterogeneous nuclear ribonucleoprotein A1(hnRNPA1)is an important RNA binding protein that regulates various RNA metabolic processes,including transcription,selective splicing of pre-mrna,translation,miRNA processing,and mRNA stability.Hn RNPA1 selectively regulates mRNA splicing processes,promotes the expression of specific protein variants associated with tumorigenesis and cancer progression,and regulates the transcription and translation of several oncogenes or anticancer genes.Inhibitors targeting hnRNPA1 have always been concern and studied.VPC-80051,an hnRNPA1 inhibitor developed through computer-aided drug design to target the RNA binding domain(RBD)of hnRNPA1,a compound that effectively inhibits c-Myc transcription and alternative splicing variants generated by the androgen receptor(AR-V1)regulated by hnRNPA1.Developing drugs targeting hnRNPA1 faces challenges in terms of targeting specificity,side effects,and drug delivery efficiency.In this paper,chemical modification optimization was carried out based on compound VPC-80051,and the method of computer-aided drug design was also used to preliminatively predict the activity of the compound.After molecular docking scoring,the top 24 compounds were selected for synthesis and identification.Three small molecule compounds with significantly better activity than VPC-80051 were obtained through in vitro anti-tumor activity study.According to the different advantages and disadvantages of the three compounds,further pharmacologic or pharmacological studies can be conducted.This paper aims to lay a foundation for future research on the development of small molecule inhibitors targeting hnRNPA1 and the molecular mechanism of inhibition of hnRNPA1.