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.