Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-17 , DOI: 10.1021/acs.jmedchem.2c01517
Silong Zhang _{1,

2} , Yu Zhang ₁ , Xin Chen ₃ , Juan Xu _{2,

4} , Huaxiang Fang ₂ , Yuanyuan Li _{2,

3} , Yi Liu _{1,

3,

5} , Huan He _{1,

2}

Affiliation

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1–KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven cancer.

中文翻译：

用于治疗 KRAS 驱动癌的口服生物可利用 SOS1 抑制剂的设计和结构优化

KRAS 突变（G12C、G12D 等）与许多难治性癌症的发生和发展有关。Son of sevenless homolog 1 (SOS1) 是 KRAS 的关键调节因子，可将 KRAS 从非活性状态调节为活性状态。在此，我们公开了提高功效的四环喹唑啉衍生物作为抑制 SOS1-KRAS 相互作用的增强支架。将 1-腈-环丙烷与四环喹唑啉缀合的化合物37在 CD-1 小鼠血浆中表现出比 BI-3406 高两倍的口服药物暴露和长 2.5 倍的半衰期。在 Mia-paca-2 异种移植模型中，单独给药37抑制了 71% 的肿瘤生长。临床前研究表明，37对 CYP 和 hERG 的抑制有限。总的来说，我们的研究表明37是治疗 KRAS 驱动的癌症的有前途的候选药物。

更新日期：2022-11-17

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11