Pharmacological inhibition of the human ACSS-2 protein for therapeutic intervention with Breast Cancer Brain Metastatic Tumor (BCBM) Growth

Overview

Drexel researchers in the College of Medicine have developed novel small-molecule inhibitors targeting the ACSS-2 enzyme to treat cancer, especially brain metastases of breast cancer.

This technology involves a series of newly developed small-molecule compounds that inhibit acyl-coenzyme A synthetase short family member 2 (ACSS2), an enzyme essential for cancer cell metabolism and survival. By blocking ACSS2, these inhibitors disrupt acetate metabolism, which is critical for tumor proliferation and cell survival, particularly in aggressive cancers such as breast cancer brain metastases. The lead compounds demonstrate improved drug-like properties, blood-brain barrier penetration, and strong anti-tumor efficacy in cellular, organotypic, and animal models.

Market Applications

Treatment of breast cancer brain metastases (BCBM) and other brain cancers.
Combination therapies with radiation or other standard-of-care cancer treatments.
Development of targeted metabolic inhibitors in oncology.
Pharmaceutical pipelines focusing on novel anti-cancer therapeutics.
Potential extension to other cancers exhibiting upregulated ACSS2 activity.

Key Advantages

Targeted and selective inhibition of a cancer cell-specific metabolic enzyme (ACSS2, and not ACSS1).
Effective in harsh, hypoxic tumor microenvironments like brain metastases.
Improved potency and metabolic stability of inhibitors.
Ability to cross the blood-brain barrier with low susceptibility to efflux, enabling treatment of intracranial tumors.
Validated binding affinity, kinetics, and mechanism of action.
Synergistic effects when combined with radiation therapy.
Demonstrated low toxicity in preclinical animal studies.

Problems Solved

Overcoming metabolic adaptations of cancer cells that promote growth and survival.
Addressing breast cancer brain metastases, including triple-negative subtypes that are resistant to conventional therapies.
Reducing tumor growth in difficult-to-treat intracranial environments.
Providing a novel therapeutic option for cancers reliant on acetate metabolism.
Minimizing toxicity while effectively inhibiting tumor progression.