AUTHOR=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 TITLE=Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells JOURNAL=Frontiers in Pharmacology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1394685 DOI=10.3389/fphar.2024.1394685 ISSN=1663-9812 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.