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Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK) that has been shown to reverse the Warburg effect and cause tumor cell death. Clinical research into the anti-cancer activity of DCA revealed high dosage requirements and reports of toxicity. While there have been subsequent mechanistic investigations, a search for DCA alternatives could result in a safer and more effective anticancer therapy. This study evaluates eight small compounds with a conserved dichloric terminal and their in vitro and in vivo potential for anticancer activity. Initial viability screening across six cancer cell lines reveals even at 10 mg/mL, compound treatments do not result in complete cell death which suggests minimal compound cytotoxicity. Furthermore, in vivo data demonstrates that cationic dichloric compounds DCAH and DCMAH, which were selected for further testing based on highest in vitro viability impact, inhibit tumor growth in the U87 model of glioblastoma, suggesting their clinical potential as accessible anti-cancer drugs. Immunoblotting signaling data from tumor lysates demonstrates that the mechanism of actions of cationic DCAH and DCMAH are unlikely to be consistent with that of the terminally carboxylic DCA and warrants further independent investigation.

A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6–16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R(1), R(2), and R(3)). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC(50) = 420 nM) and 9 (IC(50) = 930 nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-D-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors.