The Comparative Metabolism of a Novel Hepatocellular Carcinoma Therapeutic Agent, 2,3-Diamino- N -(4-(benzo[d]thiazol-2-yl)phenyl)propanamide, in Human and Animal Hepatocytes

• Published in: Metabolites Vol. 14; no. 8; p. 425
• Main Authors: Jung, Young-Heun, Lee, Dong-Cheol, Kwon, Ye-Min, Jang, Eunbee, Choi, Garam, Kim, Yeoun-Hee, Kim, Tae Hwan, Kim, Ju-Hyun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024; MDPI
• Subjects: Acetylation; Acetyltransferase; Cancer therapies; CYP; CYP1A2 protein; Cytochrome P450; Cytosol; Enzymes; ETN101; Hepatocellular carcinoma; hepatocyte; Hepatocytes; Kinases; Liquid chromatography; Liver cancer; Liver cirrhosis; Liver diseases; Mass spectroscopy; Metabolism; Metabolites; N-Acetyltransferase; N-acetyltransferase 1; N-Acetyltransferase 2; NAT; Toxicity; Tumors; United States > US; South Korea; NAT; ETN101; metabolism; hepatocyte; CYP; hepatocellular carcinoma
• ISSN: 2218-1989; 2218-1989
• DOI: 10.3390/metabo14080425

[2,3-diamino- -(4-(benzo[d]thiazol-2-yl)phenyl)propanamide], named as ETN101, is a novel therapeutic agent for hepatocellular carcinoma. In vitro studies examined ETN101 metabolites in human, mouse, rat, dog, and monkey hepatocytes and identified the drug-metabolizing enzymes involved using cDNA-expressed human recombinant cytochrome P450s (CYPs), carboxylesterases (CESs), -acetyltransferase (NAT) 1, and human liver cytosol. ETN101 showed similar metabolic stability across hepatocytes from five species, with particularly comparable stability in humans, rats, and monkeys. Its half-life was 75.0 min in humans, 68.9 in rats, 73.1 in monkeys, 120.4 in mice, and 112.7 in dogs. Thirty-four ETN101 metabolites, including the major metabolite M1, were identified using liquid chromatography-high-resolution mass spectrometry. ETN101 was primarily metabolized to M1 and CYP1A2 is exclusively responsible for M1 metabolism. Both NAT1 and NAT2 were responsible for the -acetylation of M1 to M2. ETN101 remained stable in human CESs. In conclusion, this study provides comprehensive insights into the metabolic characteristics of ETN101, valuable for its toxicological and clinical development.