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

On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47phox (p47), we designed a mimetic of the tripeptide PPP based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSNPPPRPPA 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. This is a first example of the use of a triproline mimetic to interfere with the formation of the p47-p22 complex, which is critical for the activation of NOX, leading to the production of reactive oxygen species as superoxide anions.

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

Following the identification of thieno[2,3-d]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. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable in vivo PD response. One compound was progressed into efficacy studies and inhibited tumor growth.

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. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.

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 introduction of hindered rotation along a biaryl axis has conferred high selectivity to the compounds, and cellular activity was brought on scale by offsetting the negative charge of the anchoring carboxylate group. The obtained compounds described here exhibit nanomolar binding affinity and mechanism-based cellular efficacy, caspase induction, and growth inhibition. These early research efforts illustrate drug discovery optimization from thienopyrimidine hits to a lead compound, the chemical series leading to the identification of our more advanced compounds S63845 and S64315.

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. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

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. PATIENTS: 255 adults and children using the Advanced Bionics HiRes90k cochlear implant. INTERVENTION: Target driven fitting with the fitting to outcomes expert (FOX) system. MAIN OUTCOME MEASURES: For each patient, 66 measurable psychoacoustical outcomes were recorded several times after cochlear implantation: free field audiometry (6 measures) and speech audiometry (4), spectral discrimination (20), and loudness growth (36), defined from the A§E test battery. These outcomes were reduced to 22 summary variables. The initial results were compared with the latest results. RESULTS: The state of the fitting process could be well monitored by means of the measured variables. The use of the FOX computer assisted CI-programming significantly improved the proportion of the 22 variables on target. When recipients used the automated MAPs provided at switch-on, more than half (57%) of the 22 targets were already achieved before any further optimisation took place. Once the FOX system was applied there was a significant 24% (P < 0.001) increase in the number of targets achieved. CONCLUSIONS: This study demonstrates that it is feasible to set targets and to report on the effectiveness of a fitting strategy in terms of these targets. FOX provides an effective tool for achieving a systematic approach to programming, allowing for better optimisation of recipients' MAPs. The setting of well-defined outcome targets allowed a range of different centres to successfully apply a systematic methodology to monitoring the quality of the programming provided.

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. We show that the geometric model of a scene with a planar reflective surface is reduced to the estimation of vanishing-point for the case of an auto-epipolar (skew-symmetric) fundamental matrix. The correspondences for the vanishing-point estimation are extracted from motion statistics. The knowledge of the position of the vanishing point allows us to integrate the geometric model and the motion statistics into image foreground-extraction to separate foreground from reflections, and thus to achieve better performance. The experiments confirm the accuracy of the vanishing point and the improvement of the foreground image mask by removing reflected object parts.

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. Finally, correlated point-histories and data-set optimization lead to the matching of the different views. The method is validated by demonstrating its successful use on several real-life indoor and outdoor stereo video image-sequence pairs.

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. Determining the leading leg of the walking subject is important, and the presented method can identify this from two successive walk steps (one walk cycle). We tested the accuracy of the presented walk-detection method in a possible application: Image registration methods are presented which are applicable to multicamera systems viewing human subjects in motion.