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.
Bibliographical noteFunding Information:
We would like to thank Lingang Laboratory (LG-QS-202205-04 to T.X.; LG-QS-202204-01 to S.Z.), the National Natural Science Foundation of China (T2225002 to M.Z.), and the Natural Science Foundation of Shanghai (22ZR1474300 to S.Z.) for their financial support.
© 2023 American Chemical Society.
- KRAS mutation
- SOS1 inhibitor
- SOS1-KRAS interaction
- combination therapy
PubMed: MeSH publication types
- Journal Article