Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics.

On the basis of the knowledge that the proline-rich hot spot RPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22 (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47 (p47), we designed a mimetic of the tripeptide based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSNRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive.

The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

Following the identification of thieno[2,3-]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned.

Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor.

Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1.

Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity.

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation when observed in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy, has emerged as an attractive target for cancer therapy. Here, we report the discovery of selective small molecule inhibitors of Mcl-1 that inhibit cellular activity. Fragment screening identified thienopyrimidine amino acids as promising but nonselective hits that were optimized using nuclear magnetic resonance and X-ray-derived structural information.

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1.

Setting and reaching targets with computer-assisted cochlear implant fitting.

Objective: The paper aims to demonstrate the feasibility of defining a substantial set of psychoacoustic outcome measures with preset targets and to adopt a systematic methodology for reaching these targets in a large group of subjects, by more than one clinical centre.

Design: Retrospective data analysis.

Setting: Multicentre with 14 participating centres.

The use of vanishing point for the classification of reflections from foreground mask in videos.

Extraction of foreground is a basic task in surveillance video analysis. In most real cases, its performance is heavily based on the efficiency of shadow detection and on the analysis of lighting conditions and reflections caused by mirrors or other reflective surfaces. This correspondence is focused on the improvement of foreground extraction in the case of planar reflective surfaces.

Stochastic view registration of overlapping cameras based on arbitrary motion.

A new motion-based method is presented for automatic registration of images in multicamera systems, to permit synthesis of wide-baseline composite views. Unlike existing static-image and motion-based methods, our approach does not need any a priori information about the scene, the appearance of objects in the scene, or their motion. We introduce an entropy-based preselection of motion histories and an iterative Bayesian assignment of corresponding image areas.

Detection of gait characteristics for scene registration in video surveillance system.

This paper presents a robust walk-detection algorithm, based on our symmetry approach which can be used to extract gait characteristics from video-image sequences. To obtain a useful descriptor of a walking person, we temporally track the symmetries of a person's legs. Our method is suitable for use in indoor or outdoor surveillance scenes.