Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer,Journal of Medicinal Chemistry

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Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-17 , DOI: 10.1021/acs.jmedchem.3c02433
Lufeng Zheng _{1,

2} , Yuxin Zhang _{1,

2} , Shuang Mei ₁ , Tianyuan Xie _{1,

2} , Yunting Zou ₁ , Yuting Wang _{1,

2} , Han Jing _{1,

2} , Shengtao Xu ₃ , Pierre Dramou ₄ , Zhen Xu ₅ , Jindong Li ₆ , Yang Zhou ₇ , Miao-Miao Niu ₁

Affiliation

Multitarget medications represent an appealing therapy against the disease with multifactorial abnormalities─cancer. Therefore, simultaneously targeting son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR), two aberrantly expressed proteins crucial for the oncogenesis and progression of prostate cancer, may achieve active antitumor effects. Here, we discovered dual SOS1/EGFR-targeting compounds via pharmacophore-based docking screening. The most prominent compound SE-9 exhibited nanomolar inhibition activity against both SOS1 and EGFR and efficiently suppressed the phosphorylation of ERK and AKT in prostate cancer cells PC-3. Cellular assays also revealed that SE-9 displayed strong antiproliferative activities through diverse mechanisms, such as induction of cell apoptosis and G1 phase cell cycle arrest, as well as reduction of angiogenesis and migration. Further in vivo findings showed that SE-9 potently inhibited tumor growth in PC-3 xenografts without obvious toxicity. Overall, SE-9 is a novel dual-targeting SOS1/EGFR inhibitor that represents a promising treatment strategy for prostate cancer.

中文翻译：

发现用于治疗前列腺癌的 Sevenless 1 (SOS1) 和表皮生长因子受体 (EGFR) 的有效双子抑制剂

多靶点药物代表了一种针对多因素异常疾病（癌症）的有吸引力的疗法。因此，同时靶向七少子 1 (SOS1) 和表皮生长因子受体 (EGFR) 这两种异常表达的蛋白质，对前列腺癌的肿瘤发生和进展至关重要，可能会实现积极的抗肿瘤作用。在这里，我们通过基于药效团的对接筛选发现了 SOS1/EGFR 双重靶向化合物。最突出的化合物SE-9对 SOS1 和 EGFR 均表现出纳摩尔抑制活性，并有效抑制前列腺癌细胞 PC-3 中 ERK 和 AKT 的磷酸化。细胞分析还表明， SE-9通过多种机制表现出强大的抗增殖活性，例如诱导细胞凋亡和 G1 期细胞周期停滞，以及减少血管生成和迁移。进一步的体内研究结果表明， SE-9有效抑制 PC-3 异种移植物中的肿瘤生长，且无明显毒性。总体而言， SE-9是一种新型双靶点SOS1/EGFR抑制剂，代表了一种有前景的前列腺癌治疗策略。

更新日期：2024-04-17

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