SAR Studies around the SULT1A1-Activated Alkylator YC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells

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.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-09-16
DOI
https://doi.org/10.1021/acs.jmedchem.5c00489
Primary Topic
Cholangiocarcinoma and Gallbladder Cancer Studies
Type
article
Field-Weighted Citation Impact
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article

SAR Studies around the SULT1A1-Activated Alkylator YC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells

Sara E. Kearney, Amy Q. Wang, Lei Shi, Pranav Shah et al.
Journal of Medicinal Chemistry
Cholangiocarcinoma and Gallbladder Cancer Studies
article

SAR Studies around the SULT1A1-Activated Alkylator YC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells

Sara E. Kearney, Amy Q. Wang, Lei Shi, Pranav Shah, Ke Kong, Matthew D. Hall, Mindy I. Davis, Xin Xu, Olivia W. Lee, Jonathan H. Shrimp, Samarjit Patnaik, Wei Zhao, Jason M. Rohde, Jacob S. Roth, Min Shen, Tobie D. Lee, Matthew B. Boxer, Rohan Sinha, Nabeel Bardeesy, Donald W. Lewis, Marius Vava
article en

Abstract

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.

Journal of Medicinal ChemistryVol. 68(18)
Harvard University (US), Massachusetts General Hospital (US), National Center for Advancing Translational Sciences (US)
Openalex Percentile: Top 60%
Cholangiocarcinoma and Gallbladder Cancer Studies
DOIOpen Access PDFOpenAlex
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