Discovery and characterization of potent And-1 inhibitors for cancer treatment

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Acidic nucleoplasmic DNA-binding protein 1 (And-1) is crucial for DNA replication and repair.
• And-1 is overexpressed in various cancers but not in normal tissues, making it a potential therapeutic target.
• No And-1 inhibitors have been identified previously.

Purpose of the Study:

• To identify novel inhibitors of And-1.
• To investigate the mechanism of And-1 inhibition.
• To evaluate the anti-cancer efficacy of And-1 inhibitors.

Main Methods:

• High-throughput screening (HTS) of the Library of Pharmacologically Active Compounds (LOPAC) using an And-1 luciferase reporter assay.
• Secondary screening of compound analogs.
• Mechanism of action studies involving And-1 WD40 domain interaction, depolymerization, and ubiquitination via Cullin 4B (CUL4B).
• In vitro and in vivo evaluation of cancer cell growth suppression and drug re-sensitization.

Main Results:

• Two potent And-1 inhibitors, bazedoxifene acetate (BZA) and compound CH3, were identified.
• CH3 inhibits And-1 by disrupting its polymerization via direct interaction with the WD40 domain, leading to CUL4B-mediated degradation.
• CH3 suppressed the growth of diverse cancer types and re-sensitized platinum-resistant ovarian cancer cells to platinum drugs.
• BZA is an FDA-approved drug, suggesting potential for clinical trials.

Conclusions:

• Targeting And-1 with novel inhibitors represents a promising strategy for broad-spectrum cancer therapy.
• And-1 inhibitors can overcome platinum resistance in ovarian cancer.
• BZA holds potential for near-future clinical application in cancer treatment.