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Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells
Emily M Esquea1, Lorela Ciraku1, Riley G Young1
1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, United States.
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.
Insights
Researchers developed new brain-penetrant drugs targeting acetyl-CoA synthetase 2 (ACSS2) to treat breast cancer brain metastasis (BCBM). These inhibitors effectively reduced BCBM cell growth and tumor burden in preclinical models, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Breast cancer brain metastasis (BCBM) is an end-stage diagnosis with limited treatment options due to poor drug penetration into the brain.
- Brain tumors, including BCBM, utilize acetyl-CoA synthetase 2 (ACSS2) for fatty acid synthesis and protein acetylation, making it a potential therapeutic target.
Purpose of the Study:
- To identify novel, brain-penetrant inhibitors of ACSS2 for the treatment of BCBM.
- To evaluate the efficacy of identified ACSS2 inhibitors in preclinical models of BCBM.
Main Methods:
- A computational pipeline combining pharmacophore-based screening and ADME predictions was used to identify ACSS2 inhibitors.
- In vitro assays assessed the effects of compounds on BCBM cell proliferation, lipid storage, and acetyl-CoA levels.
- Ex vivo and in vivo models were used to evaluate the efficacy of ACSS2 inhibitors in reducing tumor burden and improving survival.
Main Results:
- Two novel brain-penetrant ACSS2 inhibitors, AD-5584 and AD-8007, were identified and validated for ACSS2 binding.
- AD-5584 and AD-8007 significantly reduced BCBM cell colony formation, lipid storage, acetyl-CoA levels, and cell survival in vitro.
- Treatment with AD-8007 and AD-5584 reduced pre-formed tumors in an ex vivo brain-tumor slice model, synergized with irradiation, and reduced tumor burden in vivo, extending survival.
Conclusions:
- Selective, brain-penetrant ACSS2 inhibitors demonstrate significant efficacy against breast cancer brain metastasis.
- These findings highlight ACSS2 as a viable target and present AD-5584 and AD-8007 as promising therapeutic candidates for BCBM.
