Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

The interaction between son of sevenless 1 (SOS1) gene
and Kirsten
rat sarcoma viral oncogene (KRAS) is crucial for activating signals
of proliferation and survival in a range of cancers. We previously
discovered compound 40a with a tetracyclic quinazoline
pharmacophore as a potent orally bioavailable SOS1 inhibitor. Herein,
we disclosed the discovery of compound 13c, which substituted
the third ring with the seven-membered ring, as a clinical drug candidate
for suppressing KRAS-driven tumors. 13c strongly disrupted
the protein–protein interaction between SOS1 and KRAS with
low IC50 values of 3.9 nM (biochemical) and 21 nM (cellular). 13c showed a favorable pharmacokinetic profile with a bioavailability
of 86.8% in beagles and exhibited 83.0% tumor suppression in Mia-paca-2
pancreas xenograft mice tumor models. 13c exhibited a
weak time-dependent CY3A4P inhibition than BI-3406, thereby reducing
the risk of drug–drug interaction in drug combination. Toxicological
investigations revealed that 13c had a lower risk of
sudden cardiac death than BI-3406. Overall, 13c has been
under evaluation in preclinical trials.