In Vivo Imaging of the Tumor‐Associated Enzyme NCEH1 with a Covalent PET Probe

Abstract

Herein, we report the development of an 18F‐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 18F radionuclide incorporation required for PET imaging. The resulting molecule, [18F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000‐fold selectivity relative to other serine hydrolases. [18F]JW199 displays rapid, NCEH1‐dependent accumulation in mouse tissues. Finally, we demonstrate that [18F]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.

NAD(P)‐dependent steroid dehydrogenase‐like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics

“…Using covalent PET probe imaging, they observed that NCEH1 was primarily localized to the outer edges of xenograft tissues, with less localization within the tumor. These results indicate that NCEH1 may contribute to the aggressiveness and metastasis of breast cancer cells 21 . By hydrolyzing the metabolic intermediate, 2‐acetylmonoalkylglycerol, NCEH1 may regulate the ether lipid signaling network that links platelet activating factor and lysophosphatidic acid metabolism.…”

“…Neutral cholesterol ester hydrolase 1 (NCEH1), also known as arylacetamide deacetylase‐like 1 (AADACL1) and KIAA1363, is a serine hydrolase, which has diverse biological activities and cellular functions 20‐24 . NCEH1 hydrolyzes cholesterol esters to free cholesterol, which contributes to the development of atherosclerosis.…”

“…Moreover, NCEH1 may also hydrolyze exogenous organophosphorus compounds during organ detoxification 25 . NCEH1 is overexpressed in a variety of aggressive human cancer cell lines and primary tumors 20‐23 . Although NCEH1 regulates the levels of neutral ether lipids and cholesterol ester metabolism, the manner in which these metabolites regulate the progression of cancer remains unclear.…”

Chemical Probes and Activity-Based Protein Profiling for Cancer Research

“…This probe activity showed the promising activity on blocking profibrotic response in idiopathic pulmonary fibrosis [ 27 ]. Another 18F-labeled, activity-based probe ([18F]JW199) was developed to target the cancer-associated serine hydrolase NCEH1, particularly in triple-negative breast cancer [ 28 ].…”

Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics

“…An elevated NCEH1 activity increases hydrolysis of cholesterol esters, and knockdown of NCEH1 logically induces elevated cholesterol ester levels [93,94]. Expression of NCEH1 is ubiquitous throughout the human body [95]. While a strong connection between NCEH1 and lung cancer has not been established yet, its overexpression has been linked to many cancer types including ovarian [96] and breast [97] cancers.…”