Loading...
Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells
Esquea, Emily M. Ciraku, Lorela Young, Riley G. Merzy, Jessica Talarico, Alexandra N. Ahmed, Nusaiba N. Karuppiah, Mangalam Ramesh, Anna Chatoff, Adam Crispim, Claudia V.
Esquea, Emily M.
Ciraku, Lorela
Young, Riley G.
Merzy, Jessica
Talarico, Alexandra N.
Ahmed, Nusaiba N.
Karuppiah, Mangalam
Ramesh, Anna
Chatoff, Adam
Crispim, Claudia V.
Citations
Altmetric:
Genre
Journal article
Date
2024-05-15
Advisor
Committee member
Group
Department
Cardiovascular Sciences
Permanent link to this record
Collections
Files
Research Projects
Organizational Units
Journal Issue
DOI
https://doi.org/10.3389/fphar.2024.1394685
Abstract
Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival in vitro. In an ex vivo brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival in vivo. This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis.
Description
Citation
Esquea EM, Ciraku L, Young RG, Merzy J, Talarico AN, Ahmed NN, Karuppiah M, Ramesh A, Chatoff A, Crispim CV, Rashad AA, Cocklin S, Snyder NW, Beld J, Simone NL, Reginato MJ and Dick A (2024), Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells. Front. Pharmacol. 15:1394685. doi: 10.3389/fphar.2024.1394685
Citation to related work
Frontiers Media
Has part
Frontiers in Pharmacology, Vol. 15
ADA compliance
Embedded videos
License
Attribution CC BY