Many cancer types reprogram their metabolism to become addicted to glutamine. One of the critical enzymes in the utilization of glutamine in these cells is glutaminase. CB-839 (telaglenastat) is a drug that targets glutaminase that is currently being evaluated in many clinical trials for efficacy in various cancer types that are known to be driven by glutamine metabolism. Despite its use, there are limited assays available for testing the pharmacodynamic on-target effects of CB-839 on the limited, small-volume patient samples that are obtained in early-phase clinical trials. Thus, we developed an assay based on the cellular thermal shift assay technique using AlphaLISA technology to show that CB-839 specifically engages glutaminase in colon cancer cell lines in vitro and in minute quantities of mouse xenograft tumors. Notably, we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial. This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful in future studies designed to screen other inhibitors of glutaminase.

许多癌症类型会重新编程其新陈代谢，从而对谷氨酰胺上瘾。在这些细胞中利用谷氨酰胺的关键酶之一是谷氨酰胺酶。CB-839（telaglenastat）是一种针对谷氨酰胺酶的药物，目前正在许多临床试验中评估其对已知由谷氨酰胺代谢驱动的各种癌症类型的疗效。尽管有其使用，但可用于测试 CB-839 对早期临床试验中获得的有限小体积患者样本的药效学靶向效应的测定方法有限。因此，我们使用 AlphaLISA 技术开发了一种基于细胞热位移测定技术的测定方法，以表明 CB-839 特异性地与体外结肠癌细胞系和微量小鼠异种移植肿瘤中的谷氨酰胺酶结合。值得注意的是，我们表明该测定法检测到在临床试验中接受 CB-839 时收集的患者血小板中 CB-839 与谷氨酰胺酶的结合。该测定可用于在临床试验中从患者获得的非常小的组织样本中研究 CB-839 的药效学特征，并且可能在未来旨在筛选其他谷氨酰胺酶抑制剂的研究中有用。