Department of Research Support, Yonsei Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Medicinal Chemistry & Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
Bioorg Med Chem Lett. 2022 Nov 1;75:128956. doi: 10.1016/j.bmcl.2022.128956. Epub 2022 Aug 28.
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一种新的癌症靶点，特别是针对 KRAS 和 KEAP1 共同突变的情况。使用 BPTES 报道了选择性谷氨酰胺酶 1 (GLS1) 抑制，BPTES 具有新型的别构抑制模式。然而，BPTES 是一种高度疏水且对称的分子，溶解度非常差，导致药代动力学参数不理想，阻碍了其进一步发展。作为通过对 BPTES 类似物进行系统的结构-活性关系 (SAR) 分析来识别更多类药 GLS1 抑制剂的持续努力，我们分别披露了我们用于 GLS1 抑制的新型大环化合物，对核心、核心连接子和翼连接子进行了明确的 SAR 分析。选择的分子导致 LR（LDK378 抗性）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，这些细胞共同存在包括 KRAS 和 KEAP1 在内的突变。
