Discovery of Small Molecules that Bind to Son of Sevenless 2 (SOS2)

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.

Son of Sevenless（SOS）蛋白家族包含两个高度同源的蛋白SOS1与SOS2，二者均可作为RAS蛋白的鸟苷酸交换因子（guanine nucleotide exchange factors，GEFs）发挥作用。它们可催化GDP向GTP的交换反应，进而提升RAS蛋白活性形式——GTP结合态的水平。尽管二者结构与表达模式高度相似，但学界普遍认为，在病理状态下，SOS1是介导下游信号转导的主要RAS GEF。不过，已有研究证实SOS2可对RAS-PI3K/AKT信号轴产生关键调控作用，尤其在KRAS驱动的癌细胞系以及SOS1缺失的情况下。因此，以SOS2为治疗靶点或许是靶向RAS驱动型恶性肿瘤的极具吸引力的策略。本研究报道了一类选择性喹唑啉类化合物系列的发现与初步优化过程，该类化合物可通过微摩尔级亲和力结合SOS2的催化位点。本研究同时披露了一个此前未被报道的SOS2结合位点，该位点可被另一类小分子化合物结合。