Abstract
The Son of Sevenless (SOS) protein family includes two highly homologous proteins, SOS1 and SOS2, that act as guanine nucleotide exchange factors (GEFs) for RAS proteins. They catalyze the GDP-to-GTP exchange, resulting in an increase of the active GTP-bound form of RAS. Despite highly similar structures and expression patterns, SOS1 is generally accepted as the dominant RAS GEF for downstream signaling in pathological states. Nonetheless, SOS2 has been reported to critically impact the RAS-PI3K/AKT signaling axis, especially in KRAS-driven cancer cell lines and in the absence of SOS1. Hence, therapeutic targeting of SOS2 may be an attractive strategy to target RAS-driven malignancies. Herein, we report the discovery and initial optimization of a selective quinazoline-based compound series that binds with micromolar affinity to the catalytic site of SOS2. We also disclose an additional, previously unreported binding site on SOS2 occupied by a different small molecule class.