Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells

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...

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Published in:Frontiers in pharmacology Vol. 15; p. 1394685
Main Authors: 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., Rashad, Adel A., Cocklin, Simon, Snyder, Nathaniel W., Beld, Joris, Simone, Nicole L., Reginato, Mauricio J., Dick, Alexej
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 16.05.2024
Subjects:
acetate
acetyl-CoA
brain metastasis
breast cancer
cancer
metabolism
Pharmacology
acetate
computational-aided drug design font: italic formatted: left
ACSS2
breast cancer
acetyl-CoA
brain metastasis
cancer
metabolism
ISSN:1663-9812, 1663-9812
Online Access:Get full text
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Summary: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.
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Edited by: Cody J Peer, Amgen, United States
Haixun Guo, University of Louisville, United States
Reviewed by: Bisrat G Debeb, University of Texas MD Anderson Cancer Center, United States
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2024.1394685