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

Area of Science:

• Drug discovery and development
• Medicinal chemistry
• Chemical biology

Background:

• Many biological targets remain challenging to drug (difficult-to-drug, D2D) or find ligands for (difficult-to-ligand, D2L).
• Hit-finding campaigns are crucial for identifying starting points for drug development.

Purpose of the Study:

• To analyze the success rates of various hit-finding technologies against D2D and D2L targets.
• To evaluate the utility of target stratification in predicting project success and guiding screening strategies.

Main Methods:

• Analysis of 21 hit-finding campaigns across three Roche research organizations.
• Comparison of DNA-encoded library technology (DELT), high-throughput screening, covalent screening, peptide screening, fragment screening, and virtual screening.
• Stratification of targets into D2D and D2L categories.

Main Results:

• DNA-encoded library technology (DELT) demonstrated the highest success rate in generating validated hits and lead series.
• High-throughput, covalent, and peptide screens also yielded progressable chemical matter.
• Fragment and virtual screens showed lower success rates despite generating validated hits.
• D2D targets exhibited higher rates of chemical enablement compared to D2L targets.

Conclusions:

• DELT is a valuable tool for assessing target ligandability and enabling hit discovery for challenging targets.
• Stratifying targets aids in estimating project success likelihood and optimizing hit-finding strategies.
• An integrated approach to hit discovery, tailored to target characteristics, is essential for efficient drug development.