A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

中文翻译：

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HC-7366 的发现：一种口服生物可利用且有效的 GCN2 激酶激活剂

一系列GCN2（一般控制非去阻抑2）激酶激活剂已被开发出来，最终产生HC-7366，该药物已作为抗肿瘤疗法进入临床。与原始吲唑铰链结合支架相比，优化提高了通透性，同时保持了 GCN2 的效力和 PERK（蛋白激酶 RNA 样内质网激酶）的选择性。该系列改进的 ADME 特性导致大鼠和小鼠体内化合物暴露强劲，从而允许在异种移植模型中给药 HC-7366，证明该化合物激活 GCN2 途径可抑制肿瘤生长。