Fragment expansion with NUDELs - poised DNA-encoded libraries

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Chemical Biology

Background:

• Optimizing lead compound affinity is crucial but time-consuming in drug discovery.
• Fragment-based drug discovery (FBDD) starts with low-affinity compounds, requiring significant optimization.
• Iterative fragment growing is the standard but complex and slow method for enhancing fragment potency.

Purpose of the Study:

• To introduce a novel paradigm for fragment hit optimization using poised DNA-encoded chemical libraries (DELs).
• To demonstrate the rapid discovery of potent ligands by coupling active fragments to poised DELs.
• To showcase the application of this method for optimizing fragments against bromodomain-containing protein 4 (BRD4).

Main Methods:

• Synthesis of a poised DNA-encoded chemical library (DEL) with a reactive handle.
• Coupling of a weakly binding fragment to the poised DEL via Suzuki-Miyaura cross-coupling.
• Structure-activity relationship elucidation using X-ray crystallography.

Main Results:

• Identification of a BRD4 inhibitor with 51 nM affinity in a single step, a significant potency increase.
• Demonstration that compound potency resulted from synergistic substructure combinations, difficult to find otherwise.
• The identified compound exhibited favorable lead-like properties and BRD4-dependent cellular activity.

Conclusions:

• Poised DELs offer a powerful and rapid approach for optimizing fragment hits in drug discovery.
• This method represents an attractive, generic strategy for accelerating the identification of potent drug candidates.
• The study highlights the potential of DELs to overcome key challenges in fragment-based drug discovery.