Design and Development of Potent SOS1 Inhibitors with Effective Antitumor Activities In Vitro/In Vivo

KRAS inhibitors encounter significant resistance, which may be partially mitigated through combination with SOS1 inhibitors. The structural diversity of SOS1 inhibitors presents potential solutions, offering a means to enhance treatment outcomes for KRAS mutant tumors. Herein, we report the discovery of potent SOS1 inhibitors and their antitumor activity both in vitro and in vivo. In vitro studies revealed that compound 21 exhibited potent antiproliferative activity, with IC₅₀ values of 16 nM in NCI-H358 and 17 nM in Mia Paca-2 cell proliferation assays. In the Mia Paca-2 xenograft model compound 21 exhibited significant antitumor activity with a TGI value of 38% at 12-50 mg/kg bid. Additionally, the pharmacokinetic (PK) and safety profiles of compound 21 support its potential for further development as an effective tool compound.