Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

Review of experimental methods to determine spontaneous combustion susceptibility of coal – Indian context

This paper presents a critical review of the different techniques developed to investigate the susceptibility of coal to spontaneous combustion and fire. These methods may be sub-classified into the two following areas: (1) Basic coal characterisation studies (chemical constituents) and their influence on spontaneous combustion susceptibility. (2) Test methods to assess the susceptibility of a coal sample to spontaneous combustion. This is followed by a critical literature review that summarises previous research with special emphasis given to Indian coals

MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival

Quantification of functional group interactions in transition states

A new version of the double mutant cycle approach has been used for the evaluation of weak noncovalent interactions in transition states

Substituent effects on cation-pi interactions: A quantitative study

A synthetic supramolecular complex has been adapted to quantify cation\u2013\u3c0 interactions in chloroform by using chemical double-mutant cycles. The interaction of a pyridinium cation with the \u3c0-face of an aromatic ring is found to be very sensitive to the \u3c0-electron density. Electron-donating substituents lead to a strong attractive interaction ( 128 kJ/mol 121), but electron-withdrawing groups lead to a repulsive interaction (+2 kJ/mol 121)

The role of the counteranion in the cation-pi interaction

Chemical double mutant cycles have been used to quantify cation-\u3c0 interactions in chloroform as a function of the nature of the counteranion. The cation-\u3c0 interaction is 122.5 \ub1 0.4 kJ mol 121 and independent of the anion, even though the overall stability of the complexes varies by an order of magnitude due to competition of the anion for alternative binding sites

Substituent effects on aromatic stacking interactions

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl3, and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the \u3c0-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the \u3c0-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents

MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival