- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Faculty Research and Publications /
- Computer-Aided Discovery of Small Molecules Targeting...
Open Collections
UBC Faculty Research and Publications
Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer Carabet, Lavinia A.; Leblanc, Eric; Lallous, Nada; Morin, Helene; Ghaidi, Fariba; Lee, Joseph; Rennie, Paul S.; Cherkasov, Artem
Abstract
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1–RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.
Item Metadata
| Title |
Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer
|
| Creator | |
| Contributor | |
| Publisher |
Multidisciplinary Digital Publishing Institute
|
| Date Issued |
2019-02-20
|
| Description |
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1–RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.
|
| Subject | |
| Genre | |
| Type | |
| Language |
eng
|
| Date Available |
2019-04-25
|
| Provider |
Vancouver : University of British Columbia Library
|
| Rights |
CC BY 4.0
|
| DOI |
10.14288/1.0378455
|
| URI | |
| Affiliation | |
| Citation |
Molecules 24 (4): 763 (2019)
|
| Publisher DOI |
10.3390/molecules24040763
|
| Peer Review Status |
Reviewed
|
| Scholarly Level |
Faculty
|
| Rights URI | |
| Aggregated Source Repository |
DSpace
|
Item Media
Item Citations and Data
Rights
CC BY 4.0