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.
A facile multicomponent, catalyst-free oxazolidinone synthesis from primary aliphatic or aromatic amines, dibromoethane (DBE), and the usage of either cesium carbonate or cesium hydrogencarbonate as the simultaneous base and C1 source is reported. The applicability of this technically simple reaction was demonstrated by a broad scope with generally high yields, enabling concise late-stage functionalization of amino groups into N-substituted oxazolidinones. The proposed operating reaction mechanism consists of a first-step nucleophilic substitution reaction between DBE and the primary amine, followed by the formation of a carbamate or carbonate intermediate and subsequent cyclization. Additional versatility of the herein-developed protocol has been showcased in a medicinal chemistry approach by the generation of an oxazolidinone-modified dipeptidyl peptidase 8 (DPP8) inhibitor.
Die Dipeptidylpeptidasen 8 und 9 (DPP8/9) sind aufgrund ihrer wichtigen Rolle in biologischen Prozessen wie der Immunität und Tumorgenese in den letzten Jahren in den Fokus der Wirkstoffforschung gerückt. Der individuelle Beitrag der jeweiligen Protease innerhalb dieser Prozesse ist bisher jedoch meistens noch unbekannt. Die Untersuchung ihrer individuellen Funktion kann dabei von der Verfügbarkeit Protease‐selektiver und chemisch‐diverser Hemmstoffe profitieren. In dieser Arbeit stellen wir die durch Anwendung von Aktivitäts‐basiertem Protein‐Profiling (ABPP) entdeckten 4‐Oxo‐β‐lactame als potente, nicht‐Substrat‐abgeleitete, nanomolare DPP8/9‐Inhibitoren vor. Röntgenkristallographische Untersuchungen von Liganden‐DPP‐Komplexen offenbarten dabei unterschiedliche Ligandenbindungsmodi für DPP8 und DPP9, einschließlich einer neuartigen Adressierung einer erweiterten S2′ (eS2′)‐Bindetasche in DPP8. Zusätzliche Assays bestätigten ihre Hemmwirkung sowohl auf biochemischer als auch auf zellulärer Ebene. Zusammenfassend führte unser kombinierter Ansatz aus chemischer Proteomik und strukturbasiertem Design somit zu der Entwicklung neuartiger DPP8/9‐Inhibitoren mit einem alternativem molekularen Hemmmechanismus und einem bisher nicht erreichten Selektivitätsindex.
The Front Cover illustrates the straightforward synthesis pathway leading to oxazolidinones like a highway without any curves or obstacles. With just three components, namely primary aliphatic or aromatic amines, dibromoethane, and cesium carbonate or hydrogencarbonate, a variety of oxazolidinones can be easily achieved under mild conditions and without requirement for an additional catalyst or base. Cover design by L. Sewald and L. Fehr. More information can be found in the Research Article by M. Kaiser et al.
A lone 4‐oxo‐β‐lactam molecule moves towards the catalytic site of an illuminated dipeptidyl peptidase 8 (DPP8) in a vast universe of chemical space. Achieving DPP8/9 selectivity has remained a challenge in chemical biology. The 4‐oxo‐β‐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).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.