Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties
Year: 2026
Type: article
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.
Source: Journal of Medicinal Chemistry
Institutions: Stanford University, Stanford Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: U.S. Department of Energy, American Cancer Society, Stanford University, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, Stanford Cancer Institute, SLAC National Accelerator Laboratory
Awards: G1229526393, G1286251239, 30-parameter FACSymphony A3 flow cytometer for Shared Resource Lab, G1831385526, G2371548206, G262532246, G2649945114, Targeting colorectal cancer stem cells with ALDH1B1 antagonists, G303061748, G315621713, G3629260272, 500 MHz NMR Spectrometer System with High Sensitivity Cryoprobe and Automated Sample Changer for Biochemical Research, G4235786860, G495301720, G498139845, G5570207115, G6550344761, G6775311665, G7283024673, G7823360803, Understanding the role of ALDH1B1 in gastrointestinal cancers, G8382000481, A Synchrotron Radiation Structural Biology Resource, G8925327636, Stanford Cancer Institute, Molecular Pharmacology Training Program, Chemical tools for developmental biology, G9001167340, G9001167859, G911061179
OpenAlex ID: W4414757560