Document Type

Article

Publication Date

5-16-2024

Comments

This article, first published by Frontiers Media, is the author's final published version in Frontiers in Pharmacology, Volume 15, 2024, Article number 1394685.

The published version is available at https://doi.org/10.3389/fphar.2024.1394685

Copyright © 2024 Esquea, Ciraku, Young, Merzy, Talarico, Ahmed, Karuppiah, Ramesh, Chatoff, Crispim, Rashad, Cocklin, Snyder, Beld, Simone, Reginato and 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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Table 1.PDF (158 kB)
Image 1.JPEG (281 kB)
Image 2.JPEG (408 kB)
Image 3.JPEG (493 kB)
Image 4.JPEG (410 kB)

PubMed ID

38818373

Language

English

Download

Share

COinS