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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Lavinia A CarabetArtem Cherkasov

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 hn...Continue Reading

References

Mar 9, 2002·Molecular and Cellular Biology·Angela IervolinoDanilo Perrotti
Apr 4, 2003·Journal of Medicinal Chemistry·Susan L McGovern, Brian K Shoichet
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Jan 26, 2005·Journal of Chemical Information and Modeling·John J Irwin, Brian K Shoichet
Nov 3, 2010·Genes & Development·Charles J David, James L Manley
Jan 25, 2012·Nature Chemistry·G Richard BickertonAndrew L Hopkins
Feb 14, 2012·Molecular Cell·Joao Paulo TavanezJuan Valcárcel
May 10, 2012·Journal of Computer-aided Molecular Design·Marco A C NevesRuben Abagyan
May 17, 2012·Journal of Chemical Information and Modeling·John J IrwinRyan G Coleman
Jun 7, 2012·Journal of Computer-aided Molecular Design·Mark McGann
Sep 26, 2013·International Journal of Molecular Sciences·Jacques Jean-PhilippeMassimo Caputi
May 17, 2014·Asian Journal of Andrology·Anna V LapukColin C Collins
Sep 4, 2014·The New England Journal of Medicine·Emmanuel S AntonarakisJun Luo
Sep 26, 2014·Nature·Jonathan Baell, Michael A Walters
Jan 31, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yoshiaki YamamotoMartin Gleave
Apr 4, 2015·Expert Opinion on Drug Discovery·Samuel Genheden, Ulf Ryde
Apr 22, 2015·EMBO Molecular Medicine·Alexander W Wyatt, Martin E Gleave
May 25, 2015·Journal of Molecular Biology·Christopher E MorganBlanton S Tolbert
Oct 20, 2015·Journal of Chemical Information and Modeling·Teague Sterling, John J Irwin
Nov 14, 2015·Nature Reviews. Cancer·Philip A WatsonCharles L Sawyers
Nov 20, 2015·Journal of Chemical Theory and Computation·Edward HarderRichard A Friesner
Jan 19, 2016·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Cheryl M KohErnesto Guccione
Sep 14, 2016·The International Journal of Biochemistry & Cell Biology·Marisa GranatoMara Cirone
Oct 22, 2016·Endocrine-related Cancer·Subing CaoYan Dong
Nov 27, 2016·Biochimica Et Biophysica Acta. General Subjects·Susanna CogoiLuigi E Xodo
Feb 15, 2017·Proceedings of the National Academy of Sciences of the United States of America·Niyati JainBlanton S Tolbert
Jul 22, 2017·Molecular Cancer Therapeutics·Ramakumar TummalaNagalakshmi Nadiminty
Aug 10, 2017·Wiley Interdisciplinary Reviews. RNA·Rajat RoyOlivier E Pardo

❮ Previous
Next ❯

Citations

Jul 28, 2020·International Journal of Molecular Sciences·Jessica L BellStefan Hüttelmaier
Jul 13, 2020·Journal of Hematology & Oncology·Hai QinLufeng Zheng
Aug 1, 2020·Cancers·Thao N D PhamHidayatullah G Munshi
Feb 13, 2021·Journal of Experimental & Clinical Cancer Research : CR·Hui-Er ZhuHui Chen
Feb 19, 2021·Frontiers in Oncology·Victor M Matias-BarriosXuesen Dong
Jun 3, 2021·International Journal of Molecular Sciences·Maxime BlijlevensVictor W van Beusechem

❮ Previous
Next ❯

Methods Mentioned

BETA
antisense nucleotides
X-ray
xenografts
biosensor
NMR
bio-layer interferometry
size exclusion chromatography
Assay

Software Mentioned

OPLS3
FAF
ICM
rmsd
Drugs4 ADME - Tox
OpenEye Hybrid
Maestro Desmond MD package
Glide
RESPA
QED

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.