Ras protein has been considered a fascinating target for anticancer therapy because its malfunction is closely related to cancer. However, Ras has been considered undruggable because of the failure to regulate its malfunction by controlling the Ras activation mechanism. Recently, Lumakras targeting the G12C mutation was approved, and therapeutic interest in Ras for anticancer therapy has been rejuvenated. Here, we present a series of compounds that inhibit Ras via a unique mechanism of action that exploits the relationship between the Wnt/β-catenin pathway and Ras. KYA1797K (1) binds to axin to stabilize the β-catenin destruction complex that causes the phosphorylation and subsequent degradation of Ras, similar to canonical β-catenin regulation. Based on the chemical structure of 1, we performed a structural optimization and identified 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (13d) as the most potent compound. 13d displayed antitumor effects in a colorectal cancer model with enhanced inhibition activity on Ras. The results of this study suggest that the further development of 13d could contribute to the development of Ras inhibitors with novel mechanisms of action.

Ras 蛋白一直被认为是抗癌治疗的一个迷人靶点，因为它的功能异常与癌症密切相关。然而，由于无法通过控制 Ras 激活机制来调节其故障，Ras 一直被认为是不可药用的。最近，针对 G12C 突变的 Lumakras 获得批准，Ras 在抗癌治疗中的治疗兴趣重新焕发活力。在这里，我们展示了一系列化合物，这些化合物通过利用 Wnt/β-catenin 通路与 Ras 之间关系的独特作用机制来抑制 Ras。KYA1797K (1)结合 axin 以稳定导致 Ras 磷酸化和随后降解的 β-catenin 破坏复合物，类似于典型的 β-catenin 调节。基于1的化学结构, 我们进行了结构优化并确定 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione ( 13d ) 为最有效的化合物. 13d在结直肠癌模型中显示出抗肿瘤作用，对 Ras 具有增强的抑制活性。这项研究的结果表明，13d的进一步发展可能有助于开发具有新作用机制的 Ras 抑制剂。