The application of multiple biophysical techniques to validate initial HTS hits has become an important part of lead discovery. To decipher the mode of action of a new SOS1 inhibitor class, biophysics coupled with the intensive use of structural biology was instrumental. In this case study, we targeted RAS via SOS1, its guanine nucleotide exchange factor. A combination of HTS and fragment screening resulted in the discovery of the first nanomolar SOS1 inhibitors which disrupt the interaction between RAS and SOS1.
