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Published on: March 31, 2023
Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1
Zhiping Feng1, Marisa E Hom1,2, Thomas E Bearrood1
1Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
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.
Insights
Researchers developed novel guanidine inhibitors targeting aldehyde dehydrogenases (ALDHs), specifically ALDH1B1, crucial for colorectal cancer stem cell survival. These inhibitors show promise for developing new cancer therapies by blocking tumor growth without toxicity.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Aldehyde dehydrogenases (ALDHs) are critical for cancer stem-like cell survival, making them attractive drug targets.
- ALDH1B1, a mitochondrial enzyme, is implicated in the progression of colorectal and pancreatic cancers.
Purpose of the Study:
- To discover and characterize selective inhibitors of ALDH1B1.
- To evaluate the therapeutic potential of these inhibitors in colorectal cancer models.
Main Methods:
- Design and synthesis of bicyclic imidazolium and guanidine compounds targeting ALDH1B1.
- In vitro assays to assess enzyme inhibition, cellular activity, and mitochondrial toxicity.
- Proteomic analysis and transcriptomic studies using genetic and chemical perturbations.
- Assessment of inhibitor efficacy in colon cancer spheroids and organoids.
Main Results:
- Identified potent and selective ALDH1B1 inhibitors based on guanidine and imidazolium scaffolds.
- Guanidine inhibitors demonstrated efficacy in blocking ALDH1B1 function and cancer cell growth without causing mitochondrial toxicity.
- ALDH1B1 inhibition selectively impaired the growth of colon cancer spheroids and organoids.
- Elucidated the ALDH1B1-dependent transcriptome, revealing roles in mitochondrial metabolism and ribosomal function.
Conclusions:
- ALDH1B1 plays a vital role in colorectal cancer progression.
- Developed selective guanidine-based ALDH inhibitors offer a promising therapeutic strategy.
- These compounds serve as valuable tools for further research into ALDH1B1 function in cancer.
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