Search

Remarkable progress has been made in the development of cysteine‐targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K–E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D‐targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide‐based small‐molecule inhibitors capable of inducing intramolecular cross‐linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide‐facilitated, ligand‐induced mechanism leading to intramolecular kinase cross‐linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative. [ABSTRACT FROM AUTHOR]

A novel one‐pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α‐diphenyl‐2‐pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)‐enantiomer and (2S,3S)‐enantiomer in solution, achieving a one‐pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)‐carprofen, (R,S)‐indoprofen, and (R,S)‐indobufen. The one‐pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization‐induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy. [ABSTRACT FROM AUTHOR]

A bifunctional chiral agent (BCA) strategy opens a new window to develop essential enantiomerically pure pharmaceutical products. In their Communication (e202402886), Weiwei Tang et al. report a novel crystallization‐induced deracemization method using BCA that demonstrates the dual functions of cocrystallization and catalytic racemization. This BCA strategy could address the incompatibility between cocrystallization and racemization reaction conditions...By Xin Su; Jie Sun; Jiaqiang Liu; Yaoguo Wang; Jingkang Wang; Weiwei Tang and Junbo GongReported by Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine‐reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell‐active TCIs are however available. We report herein lysine‐reactive activity‐based probes (ABPs; 2–14) based on the chemistry of aryl fluorosulfates (ArOSO2F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase‐binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X‐ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX‐680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine‐reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine‐reactive ArOSO2F‐based TCIs. [ABSTRACT FROM AUTHOR]