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Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy.

Authors :
Ran K
Li Y
Zhang YM
Tang DY
Chen ZZ
Xu ZG
Zhang L
Wang BC
Huang JH
Source :
Bioorganic chemistry [Bioorg Chem] 2024 Nov 02; Vol. 153, pp. 107929. Date of Electronic Publication: 2024 Nov 02.
Publication Year :
2024
Publisher :
Ahead of Print

Abstract

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC <subscript>50</subscript> values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC <subscript>50</subscript> value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of cancer therapy.<br />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.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1090-2120
Volume :
153
Database :
MEDLINE
Journal :
Bioorganic chemistry
Publication Type :
Academic Journal
Accession number :
39509789
Full Text :
https://doi.org/10.1016/j.bioorg.2024.107929