Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors

Meiying 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)183-190
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume14
Issue number2
DOIs
StatePublished - Feb 9 2023

Bibliographical note

Funding 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.

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • KRAS mutation
  • SOS1 inhibitor
  • SOS1-KRAS interaction
  • combination therapy

PubMed: MeSH publication types

  • Journal Article

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