posted on 2023-01-12, 18:35authored byMeiying Liu, Guizhen Zhou, Wenhong Su, Yuejiao Gu, Mingshan Gao, Kun Wang, Ruifeng Huo, Yupeng Li, Zehui Zhou, Kaixian Chen, Mingyue Zheng, Sulin Zhang, Tianfeng Xu
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.