Department of Chemistry, The University of Chicago, 929 E. 57th St., Chicago, IL, 60637, USA.
Current address: Department of Pharmacology and Chemical Biology, Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1510 Clifton Rd NE, Atlanta, GA, 30322, USA.
Angew Chem Int Ed Engl. 2020 Aug 24;59(35):15161-15165. doi: 10.1002/anie.202004762. Epub 2020 Jun 15.
Herein, we report the development of an F-labeled, activity-based small-molecule probe targeting the cancer-associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile F radionuclide incorporation required for PET imaging. The resulting molecule, [ F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000-fold selectivity relative to other serine hydrolases. [ F]JW199 displays rapid, NCEH1-dependent accumulation in mouse tissues. Finally, we demonstrate that [ F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple-negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.
在这里，我们报告了一种 F 标记的、基于活性的小分子探针的开发，该探针针对与癌症相关的丝氨酸水解酶 NCEH1。我们开展了一项集中的药物化学研究，旨在同时保持在活细胞和动物中对 NCEH1 的强烈和特异性标记，同时允许用于 PET 成像的简便 F 放射性核素掺入。所得分子[ F]JW199 以纳摩尔浓度在活细胞中标记活性 NCEH1，并相对于其他丝氨酸水解酶具有超过 1000 倍的选择性。[ F]JW199 在小鼠组织中表现出快速的、依赖于 NCEH1 的积累。最后，我们证明[ F]JW199 在体内标记侵袭性癌症肿瘤细胞，这揭示了三阴性乳腺癌肿瘤前沿的局部 NCEH1 活性，表明 NCEH1 在肿瘤侵袭性和转移中起作用。
