Abstract Introduction Epigenetic mechanisms play an important role in the initiation and advancement of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions1,2. We examined compounds from natural sources as BRD7/9 inhibitors, seeking lead candidates outside of the widely studied bromodomain and extraterminal (BET) family3. Methods As reported4,5, docking in silico involved STRAP and AutoDock Vina, ligand-protein interactions employed PDBePISA and LPC/CSU, and BROMOscan®-Bromodomain arrays were used to screen for BRD7/9 interacting compounds. BRD7/9 inhibitors also were assessed by isothermal titration calorimetry (ITC) and by anticancer activities in human colon cancer cells. Results Docking in silico identified several dietary polyphenols as potential BRD7/9 inhibitors, with binding energies ≤ -8.0 kcal/mol. BROMOscan® and ITC experiments prioritized aspalathin, orientin, epigallocatechin-3-gallate, quercetin and equol for further investigation. Treatment with selected polyphenols mimicked BRD7/9 siRNA-mediated knockdown in reducing colon cancer cell viability and inhibiting colony formation, leading to DNA damage and apoptosis induction. Normal colonic epithelial cells were unaffected by the treatments, signifying cancer-specific targeting. These findings suggest that dietary polyphenols can recognize and target BRD7/9 proteins for potential cancer interception. Acknowledgements Research supported in part by NCI grant CA122959, the John S. Dunn Foundation, and a Chancellor's Research Initiative.1)Jung G et al., Nat Rev Gastroenterol Hepatol 2020;17:111-130. 2)Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 2017;18:246-262.3)Damiani E et al., J Cancer Prev 2020;25:189-203. 4)Rajendran P et al., Cancer Res 2019;79:918-927. 5)Kapoor S et al., Cancers (Basel) 2021;13:1438. Citation Format: Sabeeta Kapoor, Roderick H. Dashwood. Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5712.