Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1

Abstract

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.

Proteomic analysis of spinal cord tissue in a rat model of cancer-induced bone pain

“…ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates, including acetaldehyde and products of lipid peroxidation ( Chen et al, 2011 ). ALDH1B1 is overexpressed in various cancers ( Zhu et al, 2022 ) and is tightly associated with tumorigenesis and therapy resistance ( Feng et al, 2022 ). Mitochondrial enzyme GATM has a role in creatine biosynthesis, acting as a dynamic reservoir of high-energy phosphate and playing an essential role in the energy metabolism of nerve tissues ( Courtoy and Henriet, 2018 ).…”

Identify compound-protein interaction with knowledge graph embedding of perturbation transcriptomics

“…These results indicate that ALDH1B1 is a promising cancer drug target. To our knowledge, imidazoliums and guanidines 54 are the only effective ALDH1B1 inhibitors. However, they lack drug-like properties and are primarily used as molecular probes to study ALDH1B1 functions.…”

The Concept of Cancer Stem Cells: Elaborating on ALDH1B1 as an Emerging Marker of Cancer Progression

“…In the same perspective, Jackson et al (2015) applied a similar methodology to Stagos et al (2010) and determined all-trans retinaldehyde as a substrate of ALDH1B1 with Km = 24.9 μΜ, implying the involvement of ALDH1B1 in the retinoic acid signaling pathway—a finding that was occasionally overlooked in studies focused on RA-related ALDHs ( Figure 7 ) [ 182 ]. Finally, recent crystallographic data by Feng et al (2022) revealed the completed tertiary and quaternary structures of ALDH1B1 [ 183 ].…”

“…Feng et al (2022) identified a group of bicyclic imidazolium that inhibited the activity of ALDH1B1 inside cells. Significantly, both the knockdown of the ALDH1B1 gene through CRISPR, as well as the inhibition of its enzymatic activity resulted in attenuated colon spheroid and xenograft tumor growth, accompanied by the downregulation of colorectal CSC markers, such as the KRT15 and DCLK1 [ 183 ]. Similarly, Lin et al (2022) reported that shikonin downregulates ALDH1B1 in a colitis-associated mouse colorectal cancer model [ 217 ].…”