2. Academic Validation
  3. Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1

Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1

  • Nat Chem Biol. 2022 Oct;18(10):1065-1075. doi: 10.1038/s41589-022-01048-w.
Zhiping Feng 1,  Marisa E Hom 1 2,  Thomas E Bearrood 1,  Zachary C Rosenthal 1,  Daniel Fernández 3 4,  Alison E Ondrus 1 5,  Yuchao Gu 6 7 8,  Aaron K McCormick 6,  Madeline G Tomaske 6,  Cody R Marshall 1,  Toni Kline 9,  Che-Hong Chen 1,  Daria Mochly-Rosen 1,  Calvin J Kuo 6,  James K Chen 10 11 12
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
  • 2 Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3 Macromolecular Structure Knowledge Center, Stanford University, Stanford, CA, USA.
  • 4 Stanford ChEM-H, Stanford University, Stanford, CA, USA.
  • 5 Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA.
  • 6 Department of Medicine, Stanford University, Stanford, CA, USA.
  • 7 Department of Biochemistry, Stanford University, Stanford, CA, USA.
  • 8 Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
  • 9 SPARK at Stanford, Stanford University, Stanford, CA, USA.
  • 10 Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA. [email protected].
  • 11 Department of Developmental Biology, Stanford University, Stanford, CA, USA. [email protected].
  • 12 Department of Chemistry, Stanford University, Stanford, CA, USA. [email protected].
PMID: 35788181 DOI: 10.1038/s41589-022-01048-w
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.

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