Pyruvate dehydrogenase kinase PDK1 is a metabolic enzyme responsible for switching glucose metabolism from mitochondrial oxidation to aerobic glycolysis in cancer cells, a general hallmark of malignancy termed the Warburg effect. Herein we report the identification of JX06 as a selective covalent inhibitor of PDK1 in cells. JX06 forms a disulfide bond with the thiol group of a conserved cysteine residue (C240) based on recognition of a hydrophobic pocket adjacent to the ATP pocket of the PDK1 enzyme. Our investigations of JX06 mechanism suggested that covalent modification at C240 induced conformational changes at Arginine 286 through Van der Waals forces, thereby hindering access of ATP to its binding pocket and in turn impairing PDK1 enzymatic activity. Notably, cells with a higher dependency on glycolysis were more sensitive to PDK1 inhibition, reflecting a metabolic shift that promoted cellular oxidative stress and apoptosis. Our findings offer new mechanistic insights including how to therapeutically target PDK1 by covalently modifying the C240 residue. Cancer Res; 75(22); 4923-36. Ó2015 AACR.

We report herein a fluoroionophore sensor derivated from tryptophan that shows high sensitivity (detection limit up to 0.15 microM) and specific selectivity for lead ion (Pb2+) over Ca2+, Cd2+, Co2+, Cr3+, Cu2+, K+, Mg2+, Na+, Fe2+, Mn2+, Ni2+ and Zn2+ in aqueous solution.

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Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k/K = 4.17 × 10 M s) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.

Background To evaluate the feasibility and safety of robot-assisted retroperitoneal laparoscopic adrenalectomy (RARLA) for large pheochromocytomas (PHEOs; size≥6 cm) compared with retroperitoneal laparoscopic adrenalectomy (RLA). Methods Fifty-one patients who underwent adrenalectomy for large PHEOs between March 2016 and January 2019 were enrolled and divided into two groups, including 32 RLA cases and 19 RARLA cases. We compared the perioperative efficacy and long-term follow-up results between the two groups. Results Preoperative data, including demographics, comorbidities and tumour characteristics, were similar between the groups. Intraoperatively, the RARLA group had a lower incidence of haemodynamic instability (26.3% vs. 56.2%, P = 0.038) and less intraoperative blood loss (100 ml vs. Two hundred milliliter, P = 0.042) than the RLA group. The groups showed no significant differences in operative time or transfusion rates. Postoperatively, the time to diet resumption, time to ambulation, time to drainage removal and postoperative hospital stay were shorter in the RARLA group than in the RLA group (1 d vs. 2 d, P = 0.027; 1 d vs. 2 d, P = 0.034; 3 d vs. 5 d, P = 0.002; 5 d vs. 6 d, P = 0.02, respectively). The groups exhibited no significant differences in the duration of anaesthetic use, complications, or long-term follow-up results for the blood pressure (BP) improvement rate. Conclusions Compared with RLA, RARLA is a safe, feasible and even optimized procedure for large PHEOs.

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Experimental investigations on the combustion performance and the stability of a dual-fuel engine fuelled with diesel and natural gas were conducted. The effects of the pilot diesel quantity and the pilot diesel injection timing were analysed. The results show that the maximum (peak) in-cylinder pressure increases and appears earlier with increasing pilot diesel quantity. The heat release rate has two peaks during the process of combustion. Earlier pilot diesel injection resulted in an earlier pressure evolution and a higher peak in-cylinder pressure. Correspondingly, the ignition of the pilot diesel was advanced and the heat release rate of diesel ignition increases. Earlier diesel injection timing increases the diesel combustion heat release, and the combustion of the whole charge in cylinder is more drastic. The pilot diesel quantities have different effects on the cycle-by-cycle variations (i.e. the coefficient of variation). At a low load, both very high and very low pilot diesel quantities lead to a high coefficient of variation in the indicated mean effective pressure, and the effect becomes weaker with increasing load. The coefficient of variation in the indicated mean effective pressure decreases and the coefficient of variation in the the peak in-cylinder pressure increases with increasing load. Additionally, the coefficient of variation in the indicated mean effective pressure decreases as the pilot diesel injection was advanced. The largest value of the coefficient of variation in the peak in-cylinder pressure occurs at 20° crank angle before top dead centre. The maximum rate of pressure rise increases dramatically with earlier pilot diesel injection timing. Nitrogen oxide emissions increase and hydrocarbon emissions decrease with increasing pilot diesel quantity. The hydrocarbon emissions decrease at earlier diesel injection timing; however, the nitrogen oxide emissions increase.

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.