Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma

KRAS mutations (G12C, G12D, etc.) are implicated in the
oncogenesis
and progression of many refractory cancers. Son of sevenless homolog
1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive
to active states. Herein, we disclosed efficacy-improving tetra-cyclic
quinazoline derivatives as an enhanced scaffold for inhibiting the
SOS1–KRAS interaction. Compound 37, which conjugated
1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a
twofold higher oral drug exposure and 2.5-fold longer half-life than
BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical
investigations demonstrated that 37 had a limited inhibition
of CYP and hERG. Overall, our studies showed that 37 was
a promising drug candidate for treatment of KRAS-driven cancer.