Novel SOS1 Inhibitors 78b and 78d Potently Suppress KRAS-Driven Colorectal Cancer Growth in Xenograft Models

Targeting KRAS-driven tumors, particularly colorectal cancer (CRC), remains a significant challenge due to the prevalence of activating KRAS mutations and the difficulty in directly inhibiting the KRAS oncoprotein. The guanine nucleotide exchange factor SOS1 has emerged as a crucial upstream regulator of KRAS, making it an attractive therapeutic target. By disrupting the interaction between SOS1 and KRAS, it's possible to inhibit downstream signaling pathways like MAPK and PI3K, which are critical for tumor proliferation and survival. Current therapies often struggle with broad efficacy across various KRAS variants, highlighting the need for pan-KRAS inhibitors.

Researchers employed a structure-based drug design strategy to develop novel quinazoline-derived molecules. They identified 78b and 78d as lead candidates, evaluating their efficacy through a series of in vitro and in vivo studies. In vitro, compounds were assessed for SOS1 binding affinity, disruption of the SOS1-KRASG12C interaction, and nucleotide exchange inhibition in both wild-type and multiple KRAS variants. 3D-antiproliferative activity was measured across a panel of CRC cell lines. For in vivo evaluation, HCT116 xenograft models were used, with compounds administered at 60 mg/kg to assess tumor growth inhibition and safety profiles at higher doses of 500 mg/kg and 700 mg/kg.

The novel quinazoline-derived compounds, 78b and 78d, exhibited high SOS1 binding affinity and potently disrupted the SOS1-KRASG12C interaction, effectively inhibiting nucleotide exchange in both wild-type and various KRAS variants. Both compounds demonstrated submicromolar 3D-antiproliferative activity across a panel of CRC cells. This activity was associated with induced G1 phase arrest and suppression of the MAPK and PI3K signaling pathways. Importantly, 78b and 78d showed favorable safety profiles, with no observed adverse effects at doses up to 500 mg/kg and 700 mg/kg, respectively. In HCT116 xenograft models, at a dose of 60 mg/kg, these compounds achieved significant tumor growth inhibition:

78b inhibited tumor growth by 75.1%, and 78d by 86.2%, both without significant toxicity.