Small Molecule Inhibitors of Activation-Induced Deaminase Decrease Class Switch Recombination in B Cells

Activation-induced
deaminase (AID) not only mutates DNA within
the immunoglobulin loci to generate antibody diversity, but it also
promotes development of B cell lymphomas. To tame this mutagen, we
performed a quantitative high-throughput screen of over 90 000
compounds to see if AID activity could be mitigated. The enzymatic
activity was assessed in biochemical assays to detect cytosine deamination
and in cellular assays to measure class switch recombination. Three
compounds showed promise via inhibition of switching in a transformed
B cell line and in murine splenic B cells. These compounds have similar
chemical structures, which suggests a shared mechanism of action.
Importantly, the inhibitors blocked AID, but not a related cytosine
DNA deaminase, APOBEC3B. We further determined that AID was continually
expressed for several days after B cell activation to induce switching.
This first report of small molecules that inhibit AID can be used
to gain regulatory control over base editors.