Novel inhibitors of bromodomain and extra-terminal domain trigger cell death in breast cancer cell lines.

Autor: Rahnasto-Rilla M; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Puumalainen T; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Karttunen V; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Adla SK; School of Pharmacy, University of Eastern Finland, Kuopio, Finland., Lahtela-Kakkonen M; School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Electronic address: Maija.Lahtela-Kakkonen@uef.fi.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Oct 01; Vol. 112, pp. 117884. Date of Electronic Publication: 2024 Aug 31.
DOI: 10.1016/j.bmc.2024.117884
Abstrakt: Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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