Analyses of Recent Hit-Finding Campaigns for Difficult Targets Provides Guidance for Informed Integrated Hit Discovery

Despite advancements in hit-finding technologies, many drug targets are considered difficult-to-drug (D2D) or difficult-to-ligand (D2L). Here, we present an analysis of 21 hit-finding campaigns across three research organizations within the Roche group, focusing on D2D and D2L targets. DNA-encoded library technology (DELT) was the most successful method in providing validated hits and lead series. High-throughput, covalent, and peptide screens also yielded progressable chemical matter in a substantial number of cases. In contrast, fragment and virtual screens, while effective in generating validated hits, demonstrated lower success rates. Stratifying targets into D2D and D2L categories provided a useful framework for estimating the likelihood of project success and informing additional screening strategies, with D2D targets showing higher rates of chemical enablement. Our findings indicate DELT as a valuable experimental tool for assessing ligandability and highlight the importance of informed integrated hit discovery by tailoring hit-finding strategies to target characteristics.