RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

We describe a new paradigm for three-dimensional computer graphics, using projectors to graphically animate physical objects in the real world. The idea is to replace a physical object-with its inherent color, texture, and material properties-with a neutral object and projected imagery, reproducing the original appearance directly on the object. Furthermore the projected imagery can be used to reproduce alternative appearances, including alternate shading, lighting, and even animation. Because the approach is to effectively "lift" the visual properties of the object into the projector, we call the projectors shader lamps .Some limited effects have previously been demonstrated along these lines for specific applications, however the real challenges to realizing this as a new medium for computer graphics lies in addressing the problems related to complete illumination of nontrivial physical objects. Our approach offers a very compelling method of visualization for a variety of applications including dynamic mechanical and architectural models, animated or "living" dioramas, artistic effects, entertainment, and even general visualization for problems that have meaningful physical shape representations. We present and demonstrate methods for using multiple shader lamps to animate physical objects of varying complexity, from a flower vase, to some wooden blocks, to a model of the Taj Mahal.

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.

We present a Dynamic Spatially Augmented Reality system for augmenting movable 3D objects in an indoor environment using multiple projectors. We describe a real-time system for applying virtual paint and textures to real objects simply by direct physical manipulation of the object and a "paint brush" stylus. We track the objects and the "paintbrush", and illuminate the objects with images that remain registered as they move, to create the illusion of material properties. The system is simple to use and we hope it may herald new applications in diverse fields such as visualization, tele-immersion, art and architecture. The system currently works with tracked objects whose geometry was pre-acquired and models created manually, but it is possible to extend it, by adding cameras to the environment, to acquire object geometry automatically and use vision-based tracking for the object and paintbrush.

Finding recurring residue packing patterns, or spatial motifs, that characterize protein structural families is an important problem in bioinformatics. To this end, we apply a novel frequent subgraph mining algorithm to three graph representations of protein threedimensional (3D) structure. In each protein graph, a vertex represents an amino acid. Vertex-residues are connected by edges using three approaches: first, based on simple distance threshold between contact residues; second using the Delaunay tessellation from computational geometry, and third using the recently developed almostDelaunay tessellation approach.Applying this approach to a set of graphs representing a protein family from the Structural Classification of Proteins (SCOP) database, we typically identify several hundred common subgraphs equivalent to common packing motifs found in the majority of proteins in the family. We also use the counts of motifs extracted from proteins in two different SCOP families as input variables in a binary classification experiment using Support Vector Machines. The resulting models are capable of predicting the protein family association with the accuracy exceeding 90 percent. Our results indicate that graphs based on both almost-Delaunay and Delaunay tessellations are more sparse than contact distance graph; yet the former afford similar accuracy of classification as the latter. The protein graph mining and classification approaches developed in this paper can be used for rapid and automated annotation of protein structures determined in structural genomics projects.

We find recurring amino-acid residue packing patterns, or spatial motifs, that are characteristic of protein structural families, by applying a novel frequent subgraph mining algorithm to graph representations of protein three-dimensional structure. Graph nodes represent amino acids, and edges are chosen in one of three ways: first, using a threshold for contact distance between residues; second, using Delaunay tessellation; and third, using the recently developed almost-Delaunay edges. For a set of graphs representing a protein family from the Structural Classification of Proteins (SCOP) database, subgraph mining typically identifies several hundred common subgraphs corresponding to spatial motifs that are frequently found in proteins in the family but rarely found outside of it. We find that some of the large motifs map onto known functional regions in two protein families explored in this study, i.e., serine proteases and kinases. We find that graphs based on almost-Delaunay edges significantly reduce the number of edges in the graph representation and hence present computational advantage, yet the patterns extracted from such graphs have a biological interpretation approximately equivalent to that of those extracted from distance based graphs.

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