Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo,Journal of Medicinal Chemistry

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Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-11 , DOI: 10.1021/acs.jmedchem.3c02135
Xudong Pang _{1,

2} , Dawei Cui ₂ , Binhua Lv ₂ , Cheng-Yun Wang ₁

Affiliation

Directly targeted KRAS inhibitors are now facing resistance problems, which might be partially solved by the combination of SOS1 inhibitors with KRAS inhibitors. However, this combination may still have some resistance mitigation potential. Comparatively, SOS1 PROTAC may have promising applications in addressing the drug resistance problem by degrading the SOS1 protein. Herein, we report the discovery of novel SOS1 PROTACs and their antitumor activity both in vitro and in vivo. In vitro studies demonstrated that degrader 4 had strong inhibitory effects on the proliferation of NCI-H358 cells with IC₅₀ of 5 nM, together with significant degradation of SOS1 protein with DC₅₀ of 13 nM. In the NCI-H358 xenograft model, degrader 4 exhibited significant antitumor activities with TGI_TV values of 58.8% at 30 mg/kg bid. The PK and safety profiles also supported degrader 4 for further studies as an effective tool compound.

中文翻译：

发现有效的 SOS1 PROTAC，对 NCI-H358 肿瘤细胞具有有效的体外/体内抗肿瘤活性

直接靶向的 KRAS 抑制剂目前面临耐药性问题，而 SOS1 抑制剂与 KRAS 抑制剂的联合应用可能会部分解决这一问题。然而，这种组合仍可能具有一定的缓解耐药性的潜力。相比之下，SOS1 PROTAC 在通过降解 SOS1 蛋白解决耐药问题方面可能具有广阔的应用前景。在此，我们报告了新型 SOS1 PROTAC 的发现及其体外和体内抗肿瘤活性。体外研究表明，degrader 4对 NCI-H358 细胞的增殖有很强的抑制作用，IC ₅₀为 5 nM，并且显着降解 SOS1 蛋白，DC ₅₀为 13 nM。在 NCI-H358 异种移植模型中，降解剂4表现出显着的抗肿瘤活性，30 mg/kg bid 时的 TGI _TV值为 58.8%。 PK 和安全性概况也支持 degrader 4作为有效的工具化合物进行进一步研究。

更新日期：2024-01-11

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