Design, Synthesis, and Biological Evaluation of 5-Amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide Derivatives as Novel and Potential MEK/RAF Complex Inhibitors Based on the “Clamp” Strategy,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of 5-Amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide Derivatives as Novel and Potential MEK/RAF Complex Inhibitors Based on the “Clamp” Strategy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-21 , DOI: 10.1021/acs.jmedchem.4c00860
Peng Wang ₁ , Yongting Yuan ₁ , Tao Yang ₁ , Yurong Zou ₁ , Minghai Tang ₁ , Ziyan Ma ₁ , Weichen Bo ₁ , Songhui Qin ₁ , Yong Chen ₁ , Tao Guo ₁ , Zhongning Guo ₁ , Jianhong Yang ₁ , Mingli Xiang ₁ , Lijuan Chen ₁

Affiliation

Herein, we described the rational drug design and synthesis of a series of 5-amino-4-fluoro-1H-benzo[d]imidazole-6-carboxamide derivatives that inhibit MEK and RAF kinases. The detailed screening cascades revealed that 16b was a preferred compound, which might act like a “clamp” to stabilize the MEK/RAF complex, thereby effectively inhibiting MEK1, BRAF, and BRAF^V600E with IC₅₀ values of 28, 3, and 3 nM, respectively. 16b possessed an excellent selectivity over other 312 human-related kinases at 1 μM. In vitro, 16b showed potent antiproliferative activities against MIA PaCa-2 (G12C KRAS), HCT116 (G13D KRAS), and C26 (G12D KRAS) cells with IC₅₀ values of 0.011, 0.079, and 0.096 μM, respectively. CoIP experiments demonstrated that 16b could induce MEK/RAF complex formation. Most importantly, in the C26 syngeneic colorectal and HCT116 mice xenograft tumor models, 16b demonstrated tumor growth inhibition of 70 and 93%, respectively, suggesting that 16b may be a promising MEK/RAF complex inhibitor and worthy of further development.

中文翻译：

基于“Clamp”策略的新型潜在MEK/RAF复合抑制剂5-氨基-4-氟-1H-苯并[d]咪唑-6-甲酰胺衍生物的设计、合成和生物学评价

在此，我们描述了一系列抑制MEK和RAF激酶的5-氨基-4-氟-1H-苯并[ d ]咪唑-6-甲酰胺衍生物的合理药物设计和合成。详细的筛选级联显示16b是优选的化合物，它可能像“夹子”一样稳定MEK/RAF复合物，从而有效抑制MEK1、BRAF和BRAF ^V600E ，IC ₅₀值为28、3和3 nM ，分别。 16b在 1 μM 浓度下比其他 312 种人类相关激酶具有优异的选择性。在体外， 16b对 MIA PaCa-2 (G12C KRAS)、HCT116 (G13D KRAS) 和 C26 (G12D KRAS) 细胞表现出有效的抗增殖活性，IC ₅₀值分别为 0.011、0.079 和 0.096 μM。 CoIP 实验表明16b可以诱导 MEK/RAF 复合物形成。最重要的是，在C26同基因结直肠和HCT116小鼠异种移植肿瘤模型中， 16b分别表现出70%和93%的肿瘤生长抑制作用，表明16b可能是一种有前途的MEK/RAF复合物抑制剂，值得进一步开发。

更新日期：2024-08-21

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