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Apolipoprotein B mRNA‐editing enzyme catalytic polypeptide like (APOBEC) DNA cytidine deaminases convert cytosine to uracil in pathogen‐related single‐stranded DNAs. Aberrant activation of APOBEC enzymes in tumour cells leads to hypermutations that drive heterogeneity and clonal evolution, which results in tumour progression and treatment adaptation. APOBEC3 family member APOBEC3B (A3B) is a promising drug target to combat drug resistance, but the discovery of potent lead compounds remained challenging. Here, we devised a BspH1 restriction enzyme‐based biosensor to measure APOBEC deaminase activity, with superior simplicity and without the need of counter assays. Using this method, we performed a proof‐of‐concept screening using series of flavonoids and dihydrochalcones, from which bona fide inhibitors of recombinant A3B were identified and further validated by isothermal titration calorimetry. Our results demonstrate the capability of the BspH1‐based biosensor as a method for HTS, and prospects of developing potent A3B inhibitors using flavonoid and dihydrochalcone backbones.

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