We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.

我们报告了新型一流 2-羟吲哚基衍生物的合成作为双 PDK1-AurA 激酶抑制剂作为治疗尤文肉瘤的新策略。最有效的化合物12适用于进行体内研究。12种的特定属性包括对磷酸肌醇依赖性激酶 1 (PDK1) 和 Aurora A (AurA) 激酶的纳摩尔抑制效力，具有可接受的体外 ADME-Tox 特性（在 2 种健康和 14 种血液和实体癌细胞系中具有细胞毒性；抑制 PDE4C1、SIRT7、HDAC4、HDAC6、HDAC8、HDAC9、AurB、CYP1A2、CYP2C9、CYP2C19、CYP2D6 和h ERG）。X 射线晶体学和对接研究确定了关键的 AurA 和 PDK1/ 12互动。最后，体外药物摄入动力学和体内 PK 似乎表明这些化合物是设计和合成 PDK1/AurA 双靶分子的有吸引力的先导结构，以进一步研究体内对抗尤文肉瘤的功效。