Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors

Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur–oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

细胞周期检查点激酶1（CHK1）抑制剂是一类潜在的癌症治疗药物，可用于增强DNA损伤剂的治疗效果。目前已开发出多种来自不同化学母核的小分子CHK1抑制剂，并与化疗药物及放射治疗联合开展临床试验评估。通过对噻吩甲酰胺脲类（TCUs，如AZD7762（1））及其相关的三唑并喹啉类（TZQs）系列化合物进行骨架跃迁改造，研究人员成功发现了稠环双环类CHK1抑制剂：7-甲酰胺基噻吩并吡啶类（7-CTPs）与7-甲酰胺基吲哚类。X射线晶体结构分析显示，存在一种关键的分子内硫-氧非共价相互作用，可使结合铰链区的甲酰胺基团以共平面方式与噻吩并吡啶母核对齐；而与吲哚NH形成的分子内氢键，同样可有效将甲酰胺基团锁定在与CHK1结合的最优构象中。对7-CTPs系列化合物进行结构优化后，研究人员获得了先导化合物44，该化合物展现出优异的类药性质，以及良好的体外与体内抗肿瘤活性。