SAR Studiesaround the SULT1A1-Activated AlkylatorYC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells

作者：Ke Kong, Wei Zhao, Jonathan H. Shrimp, Marius Vava, Rohan Sinha, Shweta Sharma, Tobie D. Lee, Jacob S. Roth, Olivia W. Lee, Devin Lewis, Sara E. Kearney, Jason M. Rohde, Mindy I. Davis, Pranav Shah, Amy Q. Wang, Xin Xu, Lei Shi, Min Shen, Matthew B. Boxer, Nabeel Bardeesy, Matthew D. Hall, Samarjit Patnaik · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00489 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Nitrogen and Sulfur Effects on Brassica、Peptidase Inhibition and Analysis

A quantitative high-throughput screen using biliary tract cancer cell lines had identified the small-molecule YC-1 as being selectively cytotoxic against the IDH1-mutant cell lines with high expression of SULT1A1. We discuss the structure-activity relationship study of YC-1 analogs and identify the key structural motifs that are essential for this cytotoxicity. We highlight the narrow SAR around the furfuryl alcohol that has been reported as a critical motif that is activated to a reactive electrophile by the sulfotransferase enzyme SULT1A1. Drug-like properties of key analogs are evaluated, including a close look at YC1 hepatic metabolism. We also show the SAR of a smaller subset of 2-choloro-4-amino benzyl alcohols from the NCI compound collection with a similar benzyl alcohol motif. We also demonstrate the ability of key analogs to act as substrates of SULT1A1 in a colorimetric biochemical assay.