Development of Next-Generation ALDH1B1 Inhibitors with Enhanced Pharmacological and Functional Properties

ALDH1B1 is a mitochondrial aldehyde dehydrogenase required for the survival of stem-like colorectal and pancreatic cancer cells. Isoform-selective guanidinyl antagonists of aldehyde dehydrogenases (IGUANAs) have been developed for ALDH1B1, and here we describe structure-activity relationship (SAR) studies of three scaffold components: 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 limitations, we have explored bioisosteres of the biaryl moiety and modifications of the guanidine core. These investigations have yielded the aryl-alkyl ether derivative IGUANA-5, a potent ALDH1B1 inhibitor that selectively blocks the growth of colon and pancreatic cancer spheroids and exhibits enhanced in vitro and in vivo pharmacological properties. Our findings establish a new class of ALDH1B1 inhibitors that could inform the advancement of anti-cancer therapies.