3-amino-1,2,4-triazine scaffolds as next-generation PDK inhibitors: Design, mechanistic insights, and efficacy in pancreatic ductal adenocarcinoma.
TL;DR
Overall, these results identify amino-triazine-based scaffolds as a promising new class of potent and selective PDK inhibitors with significant anticancer potential in pancreatic cancer.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by late diagnosis, aggressiveness, metabolic plasticity, and resistance to therapy, underscoring the need for new molecular targets. Pyruvate dehydrogenase kinases (PDKs), particularly PDK1 and PDK4, drive metabolic reprogramming and tumor progression, making them attractive therapeutic targets. However, current PDK inhibitors show limited potency and selectivity. Recent 3-amino-1,2,4-triazine derivatives have demonstrated promising PDK1/PDK4 inhibition and antiproliferative activity in PDAC cells, leading to the design of a new library of sixty triazine compounds, here in reported. Several compounds exhibited strong inhibitory activity against PDK1 and PDK4, with IC50 values ranging from 0.06 to 1.1 μM, demonstrating markedly higher potency compared to DCA and pronounced isoform selectivity. Molecular modeling and supervised molecular dynamics simulations supported these findings, revealing stable binding of representative compounds within the nucleotide-binding pocket of PDK1, involving key interactions with Asp318, Arg286, and Lys327. Functionally, the compounds displayed potent antiproliferative activity in both KRAS wild-type and mutant PDAC cell lines, with micromolar IC50 values. In three-dimensional pancreatic cancer spheroid models, the most active derivatives outperformed gemcitabine by approximately threefold and exceeded the activity of DCA-derived PDK inhibitors by ∼1.7-fold. Mechanistically, the novel amino-triazines disrupted the PDK/PDH axis, inducing a metabolic shift toward oxidative phosphorylation, impairing mitochondrial function, and triggering apoptotic cell death in KRAS-mutant PSN-1 cells. Overall, these results identify amino-triazine-based scaffolds as a promising new class of potent and selective PDK inhibitors with significant anticancer potential in pancreatic cancer.