A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor

Nature Chemical Biology
Marco P LicciardelloStefan Kubicek

Abstract

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

References

Jan 1, 1985·Annual Review of Biochemistry·J W Suttie
Mar 20, 2002·Nature Reviews. Cancer·B J Feldman, D Feldman
Jan 2, 2004·Nature Medicine·Charlie D ChenCharles L Sawyers
Mar 5, 2004·The New England Journal of Medicine·François Clavel, Allan J Hance
Aug 3, 2004·Nature Reviews. Drug Discovery·Ted T Ashburn, Karl B Thor
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jul 4, 2006·Nature Chemical Biology·Curtis R ChongDavid J Sullivan
Dec 2, 2006·Nature Reviews. Drug Discovery·John P OveringtonAndrew L Hopkins
Mar 30, 2007·Nature Clinical Practice. Oncology·Mary-Ellen Taplin
Dec 8, 2009·Science·Jan E CaretteThijn R Brummelkamp
Feb 20, 2010·Nature Reviews. Drug Discovery·Steven M PaulAaron L Schacht
Sep 15, 2010·PLoS Computational Biology·Murat IskarPeer Bork
May 27, 2011·The New England Journal of Medicine·Johann S de BonoUNKNOWN COU-AA-301 Investigators
Jun 17, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jan H ReilingDavid M Sabatini
Jul 23, 2011·Endocrine-related Cancer·Scott M Dehm, Donald J Tindall
Mar 2, 2012·Nature Reviews. Drug Discovery·Jack W ScannellBrian Warrington
May 9, 2012·International Journal of Epidemiology·Mieke Van HemelrijckUNKNOWN NPCR and PCBaSe Sweden
Jun 8, 2012·Nature Reviews. Cancer·Christoph Bock, Thomas Lengauer
Jun 30, 2012·Bioinformatics·Liguo WangWei Li
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Oct 29, 2013·Nature Methods·Tilmann BürckstümmerSebastian M B Nijman
May 2, 2014·Journal of Molecular Endocrinology·Momoe ItsumiSeiji Naito
May 31, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ziyang YuSteven P Balk
Jul 30, 2014·Nature Chemical Biology·Georg E WinterGiulio Superti-Furga
Sep 22, 2015·Frontiers in Pharmacology·Jing TangTero Aittokallio
Dec 3, 2016·Nature Reviews. Drug Discovery·Rita SantosJohn P Overington
Jan 19, 2017·Oncotarget·Ben Yi TewJeremy O Jones

❮ Previous
Next ❯

Citations

Jul 26, 2018·Future Medicinal Chemistry·Shuaishi Gao, Luhua Lai
May 9, 2019·Nucleic Acids Research·Bulat ZagidullinJing Tang
Nov 15, 2019·Nature Communications·Michael CalderaJörg Menche
Mar 11, 2020·Nature Chemical Biology·Enrico GirardiGiulio Superti-Furga
Oct 12, 2020·Journal of the American Medical Informatics Association : JAMIA·Yejin KimXiaoqian Jiang
Jan 13, 2021·Nature Protocols·Nadine SchrodeKristen J Brennand
Feb 3, 2021·Molecular and Cellular Biology·Sachiko ShibaSatoshi Inoue
Mar 16, 2021·Journal of Gastroenterology and Hepatology·Li-Yan YangMing-Rong Wang
Aug 10, 2021·Briefings in Bioinformatics·Betül Güvenç PaltunHiroshi Mamitsuka

❮ Previous
Next ❯

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.