Exploring Extended Warheads of Reversible and Irreversible Cysteine-Targeted Covalent Kinase Inhibitors

In designing covalent kinase inhibitors (CKIs), the inclusion of electrophiles as attacking warheads demands careful choreography, ensuring not only their presence on the scaffold moiety but also their precise interaction with nucleophiles in the binding sites. Given the limited number of known electrophiles, exploring adjacent chemical space to broaden the palette of available electrophiles capable of covalent inhibition, is desirable. Here, we perform a systematic analysis of the characteristics of warheads and corresponding adjacent fragments for use in CKI design. We first collect all the released cysteine-targeted CKIs from multiple databases and create one CKI dataset containing 16,961 kinase-inhibitor data points from 12,381 unique CKIs covering 146 kinases with accessible cysteines in their binding pockets. Then we analyze this dataset, focusing on the extended warheads (i.e., warheads + adjacent fragments) — including 30 common warheads and 1344 unique adjacent fragments. Thus, we provide structural insights, and delineate chemical properties, and patterns in these extended warheads. Notably, we highlight the privileged patterns observed within reversible CKIs for the popular warheads cyanoacrylamide and aldehyde. This study provides medicinal chemists with novel insights into extended warheads and a comprehensive source of adjacent fragments, thus guiding the design, synthesis, and optimization of CKIs.