Kristen rat sarcoma (KRAS) is one of the most common oncogenes in human cancers. As a guanine nucleotide exchange factor, Son of Sevenless Homologue 1 (SOS1) represents a potential therapeutic concept for the treatment of KRAS-mutant cancers because of its activation on KRAS and downstream signaling pathways. In this review, we provide a comprehensive overview of the structure, biological function, and regulation of SOS1. We also focus on the recent advances in SOS1 inhibitors and emphasize their binding modes, structure-activity relationships and pharmacological activities. We hope that this publication can provide a comprehensive compendium on the rational design of SOS1 inhibitors.

2023-02-09·ACS Medicinal Chemistry Letters

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

Article

作者: Xu, Tianfeng ; Wang, Kun ; Zhou, Zehui ; Gao, Mingshan ; Zhou, Guizhen ; Zhang, Sulin ; Liu, Meiying ; Chen, Kaixian ; Su, Wenhong ; Zheng, Mingyue ; Huo, Ruifeng ; Gu, Yuejiao ; Li, Yupeng

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.

2022-10-13·Journal of Medicinal Chemistry1区 · 医学

Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

1区 · 医学

Article

作者: Li, Yuanyuan ; Liu, Yi ; Zhang, Silong ; Xu, Juan ; He, Huan ; Fang, Huaxiang ; Zhang, Yu

The interaction between son of sevenless 1 (SOS1) gene and Kirsten rat sarcoma viral oncogene (KRAS) is crucial for activating signals of proliferation and survival in a range of cancers. We previously discovered compound 40a with a tetracyclic quinazoline pharmacophore as a potent orally bioavailable SOS1 inhibitor. Herein, we disclosed the discovery of compound 13c, which substituted the third ring with the seven-membered ring, as a clinical drug candidate for suppressing KRAS-driven tumors. 13c strongly disrupted the protein-protein interaction between SOS1 and KRAS with low IC₅₀ values of 3.9 nM (biochemical) and 21 nM (cellular). 13c showed a favorable pharmacokinetic profile with a bioavailability of 86.8% in beagles and exhibited 83.0% tumor suppression in Mia-paca-2 pancreas xenograft mice tumor models. 13c exhibited a weak time-dependent CY3A4P inhibition than BI-3406, thereby reducing the risk of drug-drug interaction in drug combination. Toxicological investigations revealed that 13c had a lower risk of sudden cardiac death than BI-3406. Overall, 13c has been under evaluation in preclinical trials.

100 项与 SOS1 inhibitors (Yuxiang) 相关的药物交易

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