Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3‑Kinase (PI3K)

The synthesis of a series of single entity, bifunctional MEK1/PI3K inhibitors achieved by covalent linking of structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive MEK inhibitor PD0325901 is described. Inhibitors displayed potent in vitro inhibition of MEK1 (0.015 50 (nM) 50 (nM) 9 and 14 in two tumor cell lines (A549, D54). Inhibitors produced dose-dependent decreased cell viability similar to the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo efficacy of 14 following oral administration was demonstrated in D54 glioma and A549 lung tumor bearing mice. Compound 14 showed a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, at 2 h postadministration by Western blot analysis, confirming the bioavailability and efficacy of this bifunctional inhibitor strategy toward combined MEK1/PI3K inhibition.

本研究报道了一系列单实体双功能MEK1/PI3K抑制剂的合成工作，该类抑制剂通过将ATP竞争性PI3K抑制剂ZSTK474与ATP非竞争性MEK抑制剂PD0325901的结构类似物进行共价连接得到。该类抑制剂在两种肿瘤细胞系（A549、D54）中展现出强效的体外MEK1抑制活性，相关活性数据为0.015 nM、50 nM、9 nM与14 nM。该类抑制剂可诱导细胞活力呈剂量依赖性下降，其效果与等效剂量的ZSTK474和PD0325901联合给药时相当。化合物14经口服给药后的体内抗肿瘤活性，在携带D54胶质瘤与A549肺癌的小鼠模型中得到了验证。经蛋白质印迹（Western blot）分析发现，化合物14在给药后2小时可分别抑制肿瘤组织中95%的ERK1/2磷酸化与67%的Akt磷酸化，这证实了该双功能抑制剂策略用于联合抑制MEK1与PI3K的生物利用度与抗肿瘤活性。