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

Sep 24, 2026

Pyruvate dehydrogenase kinases (PDKs) drive altered cancer metabolism linked to aggressiveness and therapeutic resistance, making PDKs attractive targets. Dichloroacetic acid (DCA) is an entered phase II PDK inhibitor, yet limited clinical use reflects side effects and high dosing. Here, a small library of 3-amino-1,2,4-triazine derivatives is designed via molecular hybridization and evaluated through in silico, in vitro, and in vivo assays. The compounds show potent, PDK-subtype-selective inhibition, effective ATP-site binding, and low-micromolar induction of cancer cell death, including KRAS-mutated pancreatic cancer.

LanguageEnglish

CategoryResearch & Report

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Abstract

Introduction

Article Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma Daniela Carbone 1,†, Michele De Franco 2,†, Camilla Pecoraro 1, Davide Bassani 3, Matteo Pavan 3, Stella Cascioferro 1, Barbara Parrino 1, Girolamo Cirrincione 1, Stefano Dall'Acqua 2, Stefano Moro 3, Valentina Gandin 2, * and Patrizia Diana 1, * Citation: Carbone, D.; De Franco, M.; Pecoraro, C.; Bassani, D.; Pavan, M.; Cascioferro, S.; Parrino, B.; Cirrincione, G.; Dall'Acqua, S.; Moro, S.; et al. Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma. Int. J. Mol. Sci. 2023, 24, 3679. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24043679](10.3390/ijms24043679) Academic Editor: Jörg D. Hoheisel Received: 31 December 2022 Revised: 6 February 2023 Accepted: 9 February 2023 Published: 12 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archiraﬁ 32, 90123 Palermo, Italy 2 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy 3 Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy * [Correspondence: valentina.gandin@unipd.it](Correspondence: valentina.gandin@unipd.it) (V.G.); [patrizia.diana@unipa.it](patrizia.diana@unipa.it) (P.D.)† These authors contributed equally to this work. 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. Keywords: 3-amino-1,2,4-triazine derivatives; bis-indole derivativ

FAQs

Why are pyruvate dehydrogenase kinases (PDKs) considered promising cancer targets?

PDKs are serine/threonine kinases involved in altered cancer cell metabolism that contributes to aggressiveness and resistance, so inhibiting them may disrupt tumor metabolic rewiring.

How were the 3-amino-1,2,4-triazine derivatives developed and assessed?

The study uses a molecular hybridization approach to design the derivatives, then evaluates PDK inhibitory activity using in silico, in vitro, and in vivo assays.

What therapeutic effects do the compounds show against pancreatic cancer cells?

Cell studies indicate the derivatives induce cancer cell death at low micromolar doses, with strong effectiveness against human pancreatic KRAS-mutated cancer cells, supported by mechanistic interference with the PDK/PDH axis.

Sep 24, 2026

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