Development of next-generation ALDH1B1 inhibitors with enhanced pharmacological and functional properties
7 affiliations
- 1Department of Chemistry, Stanford University, Stanford, CA, USA, 94305.
- 2Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA, 94305.
- 3Macromolecular Structure Group, Nucleus at ChEM-H, Stanford University, Stanford, CA, USA, 94305.
- 4Present address: Eckerd College, St. Petersburg, FL, USA, 33711.
- 5Sarafan ChEM-H, Stanford University, CA, USA, 94305.
- 6Stanford Innovative Medicines Accelerator, Stanford University, Stanford, CA, USA, 94305.
- 7Department of Developmental Biology, Stanford University, Stanford, CA, USA, 94305.
Abstract
ALDH1B1, a mitochondrial aldehyde dehydrogenase, is required for the survival of stem-like colorectal and pancreatic cancer cells and a promising drug target. Isoform-specific guanidinyl agonists of aldehyde dehydrogenases (IGUANAs) have been developed for ALDH1B1, and here we describe structure-activity relationship (SAR) studies of this scaffold. Our findings delineate three ligand domains and their individual SAR profiles: the bicyclic guanidine core, a substituted aryl ring that engages the catalytic site, and a biaryl group that interacts with flanking residues. We further show that previously reported IGUANAs are metabolically labile and rapidly effluxed from intestinal epithelial cells. To address these pharmacological limitations, we have explored bioisosteres of the biaryl moiety and modifications of the bicyclic guanidine core. These investigations have yielded next-generation IGUANAs that retain nanomolar potencies against ALDH1B1 while achieving enhanced metabolic stability and functional specificity. Our lead compound, IGUANA-5, is an aryl-alkyl ether derivative that selectively blocks the growth of colon and pancreatic cancer spheroids and exhibits reduced clearance and increased Cmax in mice. We have also used IGUANA-5 to elucidate the ALDH1B1-dependent transcriptome in pancreatic cancer cells, corroborating previous findings that ALDH1B1 promotes mitochondrial metabolism. Our findings establish aryl-alkyl ether-functionalized guanidines as a new class of ALDH1B1 inhibitors that could advance the development of new anti-cancer therapies.
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BibTeX
@article{tarhan2026development,
title = {{Development of next-generation ALDH1B1 inhibitors with enhanced pharmacological and functional properties}},
author = {A. Kaan Tarhan and Zhiping Feng and Daniel Fernandez and Audrey Y. Kim and Thomas E. Bearrood and Andrew Hinman and Stefania Demuro and Adrianne M. Kinsey and Nicholas R. White and James K. Chen},
journal = {Journal of medicinal chemistry},
year = {2026},
month = oct,
doi = {10.1021/acs.jmedchem.5c03612},
url = {https://doi.org/10.1021/acs.jmedchem.5c03612},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Development of next-generation ALDH1B1 inhibitors with enhanced pharmacological and functional properties
AU - A. Kaan Tarhan
AU - Zhiping Feng
AU - Daniel Fernandez
AU - Audrey Y. Kim
AU - Thomas E. Bearrood
AU - Andrew Hinman
AU - Stefania Demuro
AU - Adrianne M. Kinsey
AU - Nicholas R. White
AU - James K. Chen
PY - 2026
DA - 2026/10/22
JO - Journal of medicinal chemistry
DO - 10.1021/acs.jmedchem.5c03612
UR - https://doi.org/10.1021/acs.jmedchem.5c03612
AB - ALDH1B1, a mitochondrial aldehyde dehydrogenase, is required for the survival of stem-like colorectal and pancreatic cancer cells and a promising drug target. Isoform-specific guanidinyl agonists of aldehyde dehydrogenases (IGUANAs) have been developed for ALDH1B1, and here we describe structure-activity relationship (SAR) studies of this scaffold. Our findings delineate three ligand domains and their individual SAR profiles: the bicyclic guanidine core, a substituted aryl ring that engages the catalytic site, and a biaryl group that interacts with flanking residues. We further show that previously reported IGUANAs are metabolically labile and rapidly effluxed from intestinal epithelial cells. To address these pharmacological limitations, we have explored bioisosteres of the biaryl moiety and modifications of the bicyclic guanidine core. These investigations have yielded next-generation IGUANAs that retain nanomolar potencies against ALDH1B1 while achieving enhanced metabolic stability and functional specificity. Our lead compound, IGUANA-5, is an aryl-alkyl ether derivative that selectively blocks the growth of colon and pancreatic cancer spheroids and exhibits reduced clearance and increased Cmax in mice. We have also used IGUANA-5 to elucidate the ALDH1B1-dependent transcriptome in pancreatic cancer cells, corroborating previous findings that ALDH1B1 promotes mitochondrial metabolism. Our findings establish aryl-alkyl ether-functionalized guanidines as a new class of ALDH1B1 inhibitors that could advance the development of new anti-cancer therapies.
SN - 0022-2623
SN - 1520-4804
ER -