作为强效SOS1抑制剂的吡啶并[2,3 - ]嘧啶 - 7 - 酮的设计、合成及生物学评价
Design, Synthesis, and Bioevaluation of Pyrido[2,3-]pyrimidin-7-ones as Potent SOS1 Inhibitors.
作者信息
Liu Meiying, Zhou Guizhen, Su Wenhong, Gu Yuejiao, Gao Mingshan, Wang Kun, Huo Ruifeng, Li Yupeng, Zhou Zehui, Chen Kaixian, Zheng Mingyue, Zhang Sulin, Xu Tianfeng
机构信息
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
出版信息
ACS Med Chem Lett. 2023 Jan 12;14(2):183-190. doi: 10.1021/acsmedchemlett.2c00490. eCollection 2023 Feb 9.
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-]pyrimidin-7-one scaffold. One representative compound showed comparable activities to the reported SOS1 inhibitor BI-3406 in both the biochemical assay and the 3-D cell growth inhibition assay. Compound 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.
使用小分子调节剂靶向鸟嘌呤核苷酸交换因子SOS1已被证明是治疗各种KRAS驱动癌症的一种有前景的策略。在本研究中，我们设计并合成了一系列具有吡啶并[2,3 -]嘧啶 - 7 - 酮骨架的新型SOS1抑制剂。一种代表性化合物在生化测定和3D细胞生长抑制测定中显示出与报道的SOS1抑制剂BI - 3406相当的活性。化合物对一组KRAS G12突变癌细胞系具有良好的细胞活性，并在MIA PaCa - 2和AsPC - 1细胞中抑制下游ERK和AKT激活。此外，当与KRAS G12C或G12D抑制剂联合使用时，它显示出协同抗增殖作用。对新化合物的进一步修饰可能会为我们提供一种有前景的SOS1抑制剂，其具有良好的类药性质，可用于治疗KRAS突变患者。
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