Files and links (1)
Published, Version of Record (VoR)CC BY V4.0, Open
Journal article
Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells
Frontiers in pharmacology, v 15, 1394685
01 May 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Metrics
Details
- Title
- Selective and brain-penetrant ACSS2 inhibitors target breast cancer brain metastatic cells
- Creators
- Emily M. Esquea - Drexel UniversityLorela Ciraku - Drexel UniversityRiley G. Young - Drexel UniversityJessica Merzy - Drexel UniversityAlexandra N. Talarico - Drexel UniversityNusaiba N. Ahmed - Drexel University, College of MedicineMangalam Karuppiah - Drexel UniversityAnna Ramesh - Drexel UniversityAdam Chatoff - Temple UniversityClaudia V. Crispim - Temple UniversityAdel A. Rashad - Drexel UniversitySimon Cocklin - Drexel UniversityNathaniel W. Snyder - Temple UniversityJoris Beld - Drexel UniversityNicole L. Simone - Pancreatic Cancer Action NetworkMauricio J. Reginato - Drexel UniversityAlexej Dick - Drexel University
- Publication Details
- Frontiers in pharmacology, v 15, 1394685
- Publisher
- Frontiers Media S.A
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology; College of Medicine; A.J. Drexel Autism Institute
- Web of Science ID
- WOS:001234849000001
- Scopus ID
- 2-s2.0-85194700839
- Other Identifier
- 991021881399504721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy