Virtual screening for novel Atg5–Atg16 complex inhibitors for autophagy modulation

Robinson, Elizabeth; Leung, Euphemia; Matuszek, Anna M.; Krogsgaard-Larsen, Niels; Furkert, Daniel P.; Brimble, Margaret A.; Richardson, Alan; Reynisson, Jóhannes

Abstract

Two hit compounds (14 and 62) were identified using virtual high throughput screening (vHTS) inhibiting the autophagy process in A2780 ovarian cancer cells. The expression levels of the LC3-II and p62 autophagy marker proteins were monitored using Western blotting. Preliminary structure activity relationship (SAR) study of close structural analogues revealed another active compound 38. The three active compounds were tested in the MCF-7 human breast cancer cells and severe reduction of autophagosomes formation was observed confirming the activity of the inhibitors. The docking scaffold used for the vHTS was a lipophilic cleft on the Atg5 protein, which is occupied by a phenylalanine residue in the Atg16 polypeptide. To the best of our knowledge this is the first report on inhibitors that specifically modulate autophagy by directly inhibiting autophagy specific proteins, which is significant due the role autophagy plays in a number of morbid diseases such as cancer.

• Journal Article Type: Article
• Acceptance Date: Oct 31, 2014
• Online Publication Date: Nov 3, 2014
• Deposit Date: Jun 13, 2023
• Journal: MedChemComm
• Print ISSN: 2040-2503
• Electronic ISSN: 2040-2511
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 1
• Pages: 239-246
• DOI: https://doi.org/10.1039/c4md00420e
• Keywords: Pharmaceutical Science; Biochemistry; Drug Discovery; Molecular Medicine; Pharmacology; Organic Chemistry
• Additional Information: : This document is Similarity Check deposited; : Supplementary Information; : The Royal Society of Chemistry has an exclusive publication licence for this journal; OPEN ACCESS: The accepted version of this article will be made freely available after a 12 month embargo period; : Single-blind; : Received 19 September 2014; Accepted 31 October 2014; Accepted Manuscript published 3 November 2014; Advance Article published 7 November 2014; Version of Record published 5 January 2015