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

doi:10.1021/acsmedchemlett.2c00490

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

ACS Med Chem Lett. 2023 Jan 12;14(2):183-190. doi: 10.1021/acsmedchemlett.2c00490. eCollection 2023 Feb 9.

Authors

Meiying Liu^{1

2}, Guizhen Zhou^{1

3}, Wenhong Su^{2

4}, Yuejiao Gu^{2

5}, Mingshan Gao², Kun Wang^{1

2}, Ruifeng Huo³, Yupeng Li⁶, Zehui Zhou^{2

5}, Kaixian Chen^{1

3

5}, Mingyue Zheng^{3

5

7}, Sulin Zhang³, Tianfeng Xu^{1

2

5

7}

Affiliations

¹ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
² Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁴ Nano Science and Technology Institute, University of Science and Technology of China, Suzhou 215123, China.
⁵ University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ Masonic Cancer Center & Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
⁷ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.

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.