Karim Bennaceur

Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency

Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

Microscopic determination of the nuclear incompressibility within the nonrelativistic framework

The nuclear incompressibility

Immunosuppressive networks in the tumour environment and their effect in dendritic cells

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Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome: Disease-Associated or an Epiphenomenon?

is deduced from measurements of the isoscalar giant monopole resonance (ISGMR) in medium-heavy nuclei, and the resulting value turns out to be model dependent. Since the considered nuclei have neutron excess, it has been suggested that the model dependence is due to the different behavior of the symmetry energy in different models. To clarify this issue, we make a systematic and careful analysis based on new Skyrme forces, which span a wide range of values for

Dendritic cells dysfunction in tumour environment

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Tensor part of the Skyrme energy density functional. II: Deformation properties of magic and semi-magic nuclei

, for the value of the symmetry energy at saturation and for its density dependence. By calculating, in a fully self-consistent fashion, the ISGMR centroid energy in

Isovector splitting of nucleon effective masses, ab initio benchmarks and extended stability criteria for Skyrme energy functionals

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T lymphocytes and fractalkine contribute to myocardial ischemia/reperfusion injury in patients

, we reach three important conclusions: (i) the monopole energy, and consequently the deduced value of

MDM2-p53 protein-protein interaction inhibitors: a-ring substituted isoindolinones.

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Different mechanisms are involved in apoptosis induced by melanoma gangliosides on human monocyte-derived dendritic cells

, depend on a well-defined parameter related to the shape of the symmetry energy curve and called