Back to Search
Start Over
Discovery and biological evaluation of biaryl acetamide derivatives as selective and in vivo active sphingosine kinase-2 inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116577. Date of Electronic Publication: 2024 Jun 08. - Publication Year :
- 2024
-
Abstract
- Sphingosine kinase 2 (SphK2) has emerged as a promising target for cancer therapy due to its critical role in tumor growth. However, the lack of potent and selective inhibitors has hindered its clinical application. Herein, we report the design and synthesis of a series of novel SphK2 inhibitors, culminating in the identification of compound 12q as a highly selective and potent inhibitor of SphK2. Molecular dynamics simulations suggest that the incorporation of larger substitution groups facilitates a more effective occupation of the binding site, thereby stabilizing the complex. Compared to the widely used inhibitor ABC294640, compound 12q exhibits superior anti-proliferative activity against various cancer cells, inducing G2 phase arrest and apoptosis in liver cancer cells HepG2. Notably, 12q inhibited migration and colony formation in HepG2 and altered intracellular sphingolipid content. Moreover, intraperitoneal administration of 12q in mice resulted in decreased levels of S1P. 12q provides a valuable tool compound for exploring the therapeutic potential of targeting SphK2 in cancer.<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 Masson SAS. All rights reserved.)
- Subjects :
- Humans
Animals
Mice
Structure-Activity Relationship
Molecular Structure
Apoptosis drug effects
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Drug Discovery
Dose-Response Relationship, Drug
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors chemical synthesis
Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Cell Proliferation drug effects
Acetamides pharmacology
Acetamides chemical synthesis
Acetamides chemistry
Drug Screening Assays, Antitumor
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 275
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38875809
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116577