Second harmonic generation detection of Ras conformational changes and discovery of a small molecule binder

Significance KRas is the most frequently mutated oncogene in human cancer, and its critical role in tumorigenesis is well established. Historical challenges in targeting KRas have led to its characterization as an “undruggable” target, but recent advances in drug discovery approaches have revealed promising avenues toward the development of small molecule Ras inhibitors. This study describes the successful implementation of second harmonic generation (SHG) as a screening platform to identify a conformational modulator of KRas that binds to a single distinct pocket. This work demonstrates how SHG screening can be applied to both the discovery and characterization of ligands for a high-value oncogenic target.