Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells
Emily M. Esquea, Lorela Ciraku, Riley G. Young, Jessica Merzy, Alexandra N. Talarico, Nusaiba N. Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia V. Crispim, Adel A. Rashad, Simon Cocklin, Nathaniel W. Snyder, Joris Beld, Nicole L. Simone, Mauricio J. Reginato, Alexej Dick
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.