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Aminopyridine analogs selectively target metastatic pancreatic cancer

Oncogene volume 41, pages 1518–1525 (2022)Cite this article

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Abstract

Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.

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Fig. 1: 6-aminopyridines are selectively active against PGDhigh.
Fig. 2: 6AP potently and selectively impairs PGDhigh tumoroid outgrowth.
Fig. 3: 6AP metabolites are bioactive.
Fig. 4: 6AP selectively impairs PGDhigh metastatic outgrowth in vivo.

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Acknowledgements

This work was supported by National Institutes of Health grants R01 CA222594 (OGM) and 5P30 DK058404 (OGM).

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Authors and Affiliations

  1. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Rana V. Smalling, Matthew E. Bechard & Oliver G. McDonald

  2. Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Jeff Duryea, Evan R. Roberts, Daniel Bilbao & Oliver G. McDonald

  3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    Philip J. Kingsley & Lawrence J. Marnett

  4. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    Shaun R. Stauffer

  5. Center for Therapeutics Discovery, Cleveland Clinic, Cleveland, OH, USA

    Shaun R. Stauffer

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Contributions

OGM conceived the study and oversaw experiments and data analysis. SRS oversaw compound design and conducted glide docking simulations. RVS and OGM performed cell culture, metabolite extractions, and HPLC studies. PJK and LJM advised and assisted with HPLC experiments. MEB, JD, DB, ERR, and OGM performed mouse experiments. MEB conducted confocal immunofluorescent imaging. OGM performed histopathologic analysis. OGM wrote the manuscript. RVS, SRS, and PJK edited the manuscript. RVS, MEB, SRS, JD, and OGM assembled the Figures. All authors agreed to the final version of the manuscript.

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Correspondence to Oliver G. McDonald.

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Smalling, R.V., Bechard, M.E., Duryea, J. et al. Aminopyridine analogs selectively target metastatic pancreatic cancer. Oncogene 41, 1518–1525 (2022). https://doi.org/10.1038/s41388-022-02183-3

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