Discovery of novel BET inhibitors by drug repurposing of nitroxoline and its analogues

Organic & Biomolecular Chemistry
Hao JiangCheng Luo

Abstract

The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists' interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC50 of 0.98 μM. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of th...Continue Reading

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Citations

Jun 27, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Adeena TahirMuhammad Muddassar
Feb 29, 2020·Recent Patents on Anti-cancer Drug Discovery·Raheel KhanQ Ping Dou
May 6, 2020·Pharmaceutics·Filipa Moreira-SilvaCarmen Jerónimo
Mar 30, 2018·Frontiers in Chemistry·Wenchao LuCheng Luo
Dec 15, 2020·Frontiers in Oncology·Michel Montalvo-CasimiroLuis A Herrera
Jan 19, 2021·European Journal of Medicinal Chemistry·Julie RossTarik Möröy
Jan 30, 2021·Bioorganic Chemistry·Rohini GuptaKamaldeep Paul
Jun 25, 2021·The Journal of Antibiotics·Maite Ibáñez de GarayoJ J L Miranda
Oct 9, 2018·Journal of Medicinal Chemistry·Kunal NepaliJing-Ping Liou

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Methods Mentioned

BETA
acetylation
histone acetylation
Assay
protein thermal shift
thermal shift
PCR
X-ray
protein

Software Mentioned

LigPrep
Quant Studio
BRD4LGR
Epik
Pipeline Pilot
Protein Preparation Wizard in Maestro
Impref
Maestro
Python
Protein Thermal [UNK]

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