Reversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads.

There has been a surge of interest in covalent inhibitors for protein kinases in recent years. Despite success in oncology, the off-target reactivity of these molecules is still hampering the use of covalent warhead-based strategies. Herein, we disclose the development of precision-guided warheads to mitigate the off-target challenge.

Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold.

For mitogen-activated protein kinases (MAPKs) a shallow surface-distinct from the substrate binding pocket-called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK D-groove cysteine via reversible covalent modification and interfere with the protein-protein interactions of MAPKs.

Site-Selective Antibody Conjugation with Dibromopyrazines.

In recent years, antibody conjugates have evolved as state-of-the-art options for diagnostic and therapeutic applications. During site-selective antibody conjugation, incomplete rebridging of antibody chains limits the homogeneity of conjugates and calls for the development of new rebridging agents. Herein, we report a dibromopyrazine derivative optimized to reach highly homogeneous conjugates rapidly and with high conversion on rebridging of trastuzumab, even providing a feasible route for antibody modification in acidic conditions.

Mapping protein binding sites by photoreactive fragment pharmacophores.

Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection.

Boronic acid inhibitors of penicillin-binding protein 1b: serine and lysine labelling agents.

Penicillin-binding proteins (PBPs) contribute to bacterial cell wall biosynthesis and are targets of antibacterial agents. Here, we investigated PBP1b inhibition by boronic acid derivatives. Chemical starting points were identified by structure-based virtual screening and aliphatic boronic acids were selected for further investigations.