Abstract

The First Discovery of a Single Digit Nanomolar Small Molecule Blocker of a Protein-protein Interaction Target

Nils Hansen, Chief Executive Officer, Vipergen ApS

Protein-protein interactions (PPI) are involved in almost all physiological processes and diseases, and hold a tremendous potential for drug development. However, discovery of small molecule blockers of PPIs has been limited due to technological hurdles, and when hits were successfully identified these had typically modest potencies in the high nanomolar to micromolar range. Here, we present efficient small molecule PPI blocker discovery using a high fidelity DNA-encoded library technology platform, which provides access to (1) drug-like and diverse chemical matter and (2) and an efficient low-noise homogeneous screening assay. The screen employs a unique principle of trapping small molecule binders together with the protein target in miniscule droplets and enables direct identification of potent inhibitors directly from the library. Case stories will be presented, including interleukin 6 receptor (IL-6R) which is a clinically validated target implicated in cancer, and multiple inflammatory and autoimmune diseases. For IL-6R, discovery of single digit nanomolar potency hits (MW ~500 Da) is demonstrated belonging to two series exhibiting clear instant structure activity relationships. The latter allows instant determination of the core motif (350 Da) which itself exhibits a potency of 16 nM. These findings represent PPI target hits with 1000 fold greater potency than any previously reported and represent a major leap forward in the endeavour to develop orally bioavailable therapeutics for this important yet untapped target class.