Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is crucial for alternative pre-mRNA splicing in cancer.
• hnRNP A1 regulates androgen receptor (AR)-V7 splice variant production, promoting castration-resistant prostate cancer (CRPC).
• c-Myc oncoprotein transcriptionally controls hnRNP A1, forming a key regulatory circuit in CRPC.

Purpose of the Study:

• To identify and characterize small molecule inhibitors of hnRNP A1 splicing activity.
• To develop a potential therapeutic strategy targeting hnRNP A1 for CRPC treatment.
• To explore the dual therapeutic potential of targeting hnRNP A1 for AR-V7 and c-Myc reduction.

Main Methods:

• Computer-aided drug discovery approach to identify hnRNP A1 inhibitors.
• Development of VPC-80051 targeting the RNA-binding domain (RBD) of hnRNP A1.
• Experimental validation of VPC-80051's interaction with hnRNP A1 RBD and its effect on AR-V7 levels in CRPC cells.

Main Results:

• VPC-80051 identified as the first small molecule inhibitor of hnRNP A1 splicing activity.
• VPC-80051 directly interacts with the hnRNP A1 RNA-binding domain.
• VPC-80051 effectively reduces AR-V7 messenger levels in the 22Rv1 CRPC cell line.

Conclusions:

• VPC-80051 represents a novel therapeutic lead for CRPC targeting hnRNP A1.
• Targeting hnRNP A1 offers a dual approach to reduce AR-V7 and c-Myc, crucial for CRPC progression.
• This study provides a foundation for developing more potent hnRNP A1 inhibitors for cancer therapy.