Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors
文献类型：期刊论文
| 作者 | Liu, Meiying6,7; Zhou, Guizhen7,8; Su, Wenhong3,6; Gu, Yuejiao5,6; Gao, Mingshan6; Wang, Kun7; Huo, Ruifeng8; Li, Yupeng1,2; Zhou, Zehui6; Chen, Kaixian5,7,8
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| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2023-01-12 |
| 页码 | 183-190 |
| 关键词 | KRAS mutation SOS1-KRAS interaction SOS1 inhibitor combination therapy |
| DOI | 10.1021/acsmedchemlett.2c00490 |
| 文献子类 | Article |
| 英文摘要 | 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-7one 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. |
| WOS关键词 | DISCOVERY ; CANCER |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000934292900001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309719]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Sulin; Xu, Tianfeng |
| 作者单位 | 1.Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA 2.Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA; 3.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China; 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China; 7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Liu, Meiying,Zhou, Guizhen,Su, Wenhong,et al. Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2023:183-190. |
| APA | Liu, Meiying.,Zhou, Guizhen.,Su, Wenhong.,Gu, Yuejiao.,Gao, Mingshan.,...&Xu, Tianfeng.(2023).Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,183-190. |
| MLA | Liu, Meiying,et al."Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS (2023):183-190. |
入库方式： OAI收割
来源：上海药物研究所
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