Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma

Abstract

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas.

Structural Manipulations of Marine Natural Products Inspire a New Library of 3-Amino-1,2,4-Triazine PDK Inhibitors Endowed with Antitumor Activity in Pancreatic Ductal Adenocarcinoma

“…Differently from what was observed for the previously described series of analogues [ 44 , 45 ], the potencies of compounds 4 and 5 are similar for both PDK1 and HSP90.…”

Reprogramming Energy Metabolism with Synthesized PDK Inhibitors Based on Dichloroacetate Derivatives and Targeted Delivery Systems for Enhanced Cancer Therapy

“…In recent years, PDK inhibitors have been developed with different structures. − Among them, N -aryl dichloroacetamide derivatives exhibit good antiproliferative activity and potential PDK inhibition. ,,− However, their potencies are still unsatisfactory. Considering the hydrophobicity of PDK binding pockets and its nearby region, optimization efforts focused on enhancement of the hydrogen bonding, hydrophobicity, and molecular flexibility.…”

“…Currently, the PDK inhibitors that have been developed are characterized by diversity in their structure (Figure ). − The primary binding sites of certain inhibitors are functional sites such as the lipoamide-binding domain (AZD7545 and Nov3r), the ATP-binding site (Radicicol, PS10, VER-246608, and M77976), the coenzyme A-binding domain (Pfz3 and phenylbutyrate), and the pyruvate-binding domain (dichloroacetic acid (DCA)) . Among these inhibitors, DCA become a star molecule and is the only inhibitor to demonstrate initial clinical efficacy in patients with glioblastoma .…”

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

“…It is well known that nitrogen-containing heterocycles are privileged structures in medicinal chemistry because their derivatives have various biological properties [ 1 ]. The importance of nitrogen heterocycles as key pharmacophoric moieties lies in the synthesis of novel anticancer compounds [ 2 , 3 , 4 , 5 , 6 ]. Indeed, the presence of different nitrogen electron-donor atoms in the structure improves the interaction with target proteins, enzymes, and receptors through the formation of several types of interactions, such as hydrogen bonds, dipole-dipole, hydrophobic interactions, van der Waals forces, and π-stacking interactions.…”