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Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity‐based protein profiling (ABPP)‐mediated discovery of 4‐oxo‐β‐lactams as potent, non‐substrate‐like nanomolar DPP8/9 inhibitors. X‐ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2′ (eS2′) subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure‐guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date. [ABSTRACT FROM AUTHOR]

Cover Picture: Chemoproteomics-Enabled Identification of 4-Oxo- -Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 (Angew. Keywords: Activity-Based Protein Profiling; Dipeptidyl Peptidases 8/9; 4-Oxo- -Lactams; Proteomics; X-Ray Diffraction EN Activity-Based Protein Profiling Dipeptidyl Peptidases 8/9 4-Oxo- -Lactams Proteomics X-Ray Diffraction 1 1 1 11/16/22 20221121 NES 221121 B A lone 4-oxo- I i -lactam molecule b moves towards the catalytic site of an illuminated dipeptidyl peptidase 8 (DPP8) in a vast universe of chemical space. The 4-oxo- I i -lactams, identified by a chemoproteomics platform as DPP8/9 inhibitors, may hold the key to the highly sought DPP8/9 selectivity via an unprecedented DPP8-specific mechanism, as demonstrated through X-ray diffraction by Markus Kaiser, Rui Moreira et al. in their Research Article (e202210498). [Extracted from the article]