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

Acidic nucleoplasmic DNA-binding protein 1 (And-1), an important factor for deoxyribonucleic acid (DNA) replication and repair, is overexpressed in many types of cancer but not in normal tissues. Although multiple independent studies have elucidated And-1 as a promising target gene for cancer therapy, an And-1 inhibitor has yet to be identified. Using an And-1 luciferase reporter assay to screen the Library of Pharmacologically Active Compounds (LOPAC) in a high throughput screening (HTS) platform, and then further screen the compound analog collection, we identified two potent And-1 inhibitors, bazedoxifene acetate (BZA) and an uncharacterized compound [(E)-5-(3,4-dichlorostyryl)benzo[c][1,2]oxaborol-1(3H)-ol] (CH3), which specifically inhibit And-1 by promoting its degradation. Specifically, through direct interaction with And-1 WD40 domain, CH3 interrupts the polymerization of And-1. Depolymerization of And-1 promotes its interaction with E3 ligase Cullin 4B (CUL4B), resulting in its ubiquitination and subsequent degradation. Furthermore, CH3 suppresses the growth of a broad range of cancers. Moreover, And-1 inhibitors re-sensitize platinum-resistant ovarian cancer cells to platinum drugs in vitro and in vivo. Since BZA is an FDA approved drug, we expect a clinical trial of BZA-mediated cancer therapy in the near future. Taken together, our findings suggest that targeting And-1 by its inhibitors is a potential broad-spectrum anti-cancer chemotherapy regimen.