The recent publication in the Journal of Medicinal Chemistry by Mirati Therapeutics, ZoBio and Inixium nicely demonstrates the power of biophysics, structural biology and fragments to address an important target in cancers originating from KRAS mutant cells. This research introduces the idea of SOS2:KRAS protein-protein interaction (PPI) inhibitors, which complement existing SOS1:KRAS inhibitors, offering a promising avenue for the inhibition of KRAS signaling in cancer therapy.

SOS1 is considered the primary guanine exchange factor (GEF) for KRAS, which results in the conversion of KRAS from the inactive, GDP-bound state, to the active GTP-bound state. Gain of function mutation in SOS1 have been found in different types of tumours (c.f. here) and multiple inhibitors of its interaction with KRAS have been presented (c.f. here, here or here). However, there is evidence that SOS2 plays an important role in mediating PI3K signalling (c.f. here and here) and in resistance to SOS1 inhibitors (here). Therefore, inhibition of SOS2-KRAS interaction could also be of therapeutic benefit.

The strategy outlined in the paper involves Fragment-Based Lead Discovery (FBLD). Through a combination of Surface Plasmon Resonance (SPR), Target Immobilized NMR Screen (TINS)  and X-ray crystallographic fragment-based screens, the researchers identified five fragment hits. Four of the hits displayed SOS2 binding KDs in the range 0.3−2mM, while SOS2 binding affinity could not be determined for the fifth compound. Further optimization of these hits, guided by X-ray cocrystal structures, will pave the way for the development of potent SOS2:KRAS PPI inhibitors, potentially offering new therapeutic options for KRAS-driven cancers and related disorders.

This study once more highlights the potential of FBLD as a powerful approach for drug discovery and exemplifies the type of expertise-based interactions the ZoBio team has with its clients.