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

Juan Alvarez-Gonzalez, Adam Yasgar, Robert W. Maul, Amanda Rieffer, Daniel J. Crawford, Daniel Salamango, Dorjbal Dorjsuren, Alexey V. Zakharov, Daniel J. Jansen, Ganesha Rai, Juan Marugan, Anton Simeonov, Reuben S. Harris, Rahul M. Kohli, Patricia J. Gearhart

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1214-1226
Number of pages13
JournalACS Pharmacology and Translational Science
Volume4
Issue number3
DOIs
StatePublished - Jun 11 2021

Bibliographical note

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.

Keywords

  • B cells
  • activation-induced deaminase
  • cellular assay
  • class switch recombination
  • high-throughput screen
  • small molecule inhibitors

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