SOS1 inhibitors (Yuxiang)

The use of small molecular modulators to target the guanine nucleotide exchange factor SOS1 has been demonstrated to be a promising strategy for the treatment of various KRAS-driven cancers. In the present study, we designed and synthesized a series of new SOS1 inhibitors with the pyrido[2,3-d]pyrimidin-7-one scaffold. One representative compound 8u showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 8u obtained good cellular activities against a panel of KRAS G12-mutated cancer cell lines and inhibited downstream ERK and AKT activation in MIA PaCa-2 and AsPC-1 cells. In addition, it displayed synergistic antiproliferative effects when used in combination with KRAS G12C or G12D inhibitors. Further modifications of the new compounds may give us a promising SOS1 inhibitor with favorable druglike properties for use in the treatment of KRAS-mutated patients.

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.