TY - JOUR
T1 - Small Molecule Inhibitors of Activation-Induced Deaminase Decrease Class Switch Recombination in B Cells
AU - Alvarez-Gonzalez, Juan
AU - Yasgar, Adam
AU - Maul, Robert W.
AU - Rieffer, Amanda E.
AU - Crawford, Daniel J.
AU - Salamango, Daniel J.
AU - Dorjsuren, Dorjbal
AU - Zakharov, Alexey V.
AU - Jansen, Daniel J.
AU - Rai, Ganesha
AU - Marugan, Juan
AU - Simeonov, Anton
AU - Harris, Reuben S.
AU - Kohli, Rahul M.
AU - Gearhart, Patricia J.
N1 - Funding Information:
We acknowledge initial contributions by Steve Finckbeiner, NHGRI, NIH. This work was partially supported through the Intramural Research Program at the National Institutes of Health, National Institute on Aging (AG000732), National Center for Advancing Translational Sciences (NCATS), and extramural support (R01-HG010646 to R.M.K. and PO1-CA234228 to R.S.H.). We would like to thank the NCATS Compound Management, Automation, ADME, and Analytical groups for their support. We thank Kyle Brimacombe at NCATS for graphic design assistance; Ajit Jadhav, Richard Eastman, and David Maloney for thoughtful discussion; and Kelli Wilson for curation of molecules and data integration. D.J.S. received salary support from the University of Minnesota Craniofacial Research Training (MinnCResT) program (NIH T90DE022732) and from an NIAID K99/R00 transition award (K99-AI147811).
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/6/11
Y1 - 2021/6/11
N2 - 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.
AB - 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.
KW - activation-induced deaminase
KW - B cells
KW - cellular assay
KW - class switch recombination
KW - high-throughput screen
KW - small molecule inhibitors
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U2 - 10.1021/acsptsci.1c00064
DO - 10.1021/acsptsci.1c00064
M3 - Article
AN - SCOPUS:85106506336
VL - 4
SP - 1214
EP - 1226
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
SN - 2575-9108
IS - 3
ER -