Development of next-generation ALDH1B1 inhibitors with enhanced pharmacological and functional properties

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.