Glutamine-addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co-occurring mutations. Selective glutaminase1 (GLS1) inhibition was reported using BPTES which has novel mode of allosteric inhibition. However, BPTES is a highly hydrophobic and symmetric molecule with very poor solubility which results in suboptimal pharmacokinetic parameters and hinders its further development. As an ongoing effort to identify more drug-like GLS1 inhibitors via systematic structure − activity relationship (SAR) analysis of BPTES analogs, we disclose our novel macrocycles for GLS1 inhibition with conclusive SAR analysis on the core, core linker, and wing linker, respectively. Selected molecules resulted in reduction in intracellular glutamate levels in LR (LDK378-resistant) cells which is consistent to cell viability result. Finally, compounds 13 selectively reduced the growth of A549 and H460 cells which have co-occurring mutations including KRAS and KEAP1.

谷氨酰胺成瘾的癌症代谢最近被认为是新的癌症靶点，特别是对于 KRAS 和 KEAP1 共同发生的突变。使用具有新型变构抑制模式的 BPTES 报告了选择性谷氨酰胺酶 1 (GLS1)抑制。然而，BPTES是一种高度疏水和对称的分子，溶解度很差，导致药代动力学参数欠佳，阻碍了其进一步发展。作为通过系统结构-活性关系识别更多类似药物的 GLS1 抑制剂的持续努力(SAR) 分析 BPTES 类似物，我们公开了我们用于 GLS1 抑制的新型大环化合物，分别对核心、核心接头和翼接头进行了结论性 SAR 分析。选定的分子导致 LR（LDK378 抗性）细胞中的细胞内谷氨酸水平降低，这与细胞活力结果一致。最后，化合物 13 选择性地降低了 A549 和 H460 细胞的生长，这些细胞具有共同发生的突变，包括 KRAS 和 KEAP1。