Priaxon AG

München, Germany

Priaxon AG

München, Germany
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[Figure not available: see fulltext.] Among numerous approaches for the synthesis of condensed heterocycles bearing a pyrazole nucleus, the intramolecular cyclization of a suitable ortho-substituted nitroaromatic and nitroheteroaromatic precursors is one of the most convenient routes. This review summarizes recent developments in the application of this approach for the synthesis of fused pyrazoles, their 1-oxides, and 1-hydroxy derivatives. © 2017 Springer Science+Business Media New York


Ulucan O.,Center for Bioinformatics | Eyrisch S.,Center for Bioinformatics | Eyrisch S.,Priaxon AG | Helms V.,Center for Bioinformatics
Current Pharmaceutical Design | Year: 2012

The conformational flexibility of protein targets is being increasingly recognized in the drug discovery and design processes. When working on a particular disease-related biochemical pathway, it is of crucial importance to carefully select druggable protein binding pockets among all those cavities that may appear transiently or permanently on the respective protein surface. In this review, we will focus on the conformational dynamics of proteins that governs the formation and disappearance of such transient pockets on protein surfaces. We will also touch on the issue of druggability of transiently formed pockets. For example, protein cavities suitable to bind small drug-like molecules show an increased pocket size and buriedness when compared to empty sites. Interestingly, we observed in molecular dynamics simulations of five different protein systems that the conformational transitions on the protein surface occur almost barrierless and large pockets are found at similar frequencies as small pockets, see below. Thus, the dynamical processes at protein surfaces are better visualized as fluid-like motion than as energetically activated events. We conclude by comparing two computational tools, EPOS and MDpocket, for identifying transient pockets in PDK1 kinase. We illustrate how the obtained results depend on the way in which corresponding pockets in different molecular dynamics snapshots are connected to each other. © 2012 Bentham Science Publishers.


Khazak V.,Priaxon Inc. | Eyrisch S.,Priaxon AG | Kato J.,University of California at Los Angeles | Kato J.,Takeda Pharmaceutical | And 3 more authors.
Enzymes | Year: 2013

MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma. © 2013 Elsevier Inc.


PubMed | Priaxon AG, University of California at Los Angeles and Priaxon Inc.
Type: | Journal: The Enzymes | Year: 2014

MCP compounds were developed with the idea to inhibit RAS/RAF interaction. They were identified by carrying out high-throughput screens of chemical compounds for their ability to inhibit RAS/RAF interaction in the yeast two-hybrid assay. A number of compounds including MCP1, MCP53, and MCP110 were identified as active compounds. Their inhibition of the RAS signaling was demonstrated by examining RAF and MEK activities, phosphorylation of ERK as well as characterizing their effects on events downstream of RAF. Direct evidence for the inhibition of RAS/RAF interaction was obtained by carrying out co-IP experiments. MCP compounds inhibit proliferation of a wide range of human cancer cell lines. Combination studies with other drugs showed that MCP compounds synergize with MAPK pathway inhibitors as well as with microtubule-targeting chemotherapeutics. In particular, a strong synergy with paclitaxel was observed. Efficacy to inhibit tumor formation was demonstrated using mouse xenograft models. Combination of MCP110 and paclitaxel was particularly effective in inhibiting tumor growth in a mouse xenograft model of colorectal carcinoma.


Eyrisch S.,Center for Bioinformatics | Eyrisch S.,Priaxon AG | Medina-Franco J.L.,Torrey Pines Institute for Molecular Studies | Helms V.,Center for Bioinformatics
Journal of Molecular Modeling | Year: 2012

Protein-protein interactions are abundant in signal transduction pathways and thus of crucial importance in the regulation of apoptosis. However, designing smallmolecule inhibitors for these potential drug targets is very challenging as such proteins often lack well-defined binding pockets. An example for such an interaction is the binding of the anti-apoptotic BIR2 domain of XIAP to the pro-apoptotic caspase-3 that results in the survival of damaged cells. Although small-molecule inhibitors of this interaction have been identified, their exact binding sites on XIAP are not known as its crystal structures reveal no suitable pockets. Here, we apply our previously developed protocol for identifying transient binding pockets to XIAPBIR2. Transient pockets were identified in snapshots taken during four different molecular dynamics simulations that started from the caspase-3:BIR2 complex or from the unbound BIR2 structure and used water or methanol as solvent. Clustering of these pockets revealed that surprisingly many pockets opened in the flexible linker region that is involved in caspase-3 binding. We docked three known inhibitors into these transient pockets and so determined five putative binding sites. In addition, by docking two inactive compounds of the same series, we show that this protocol is also able to distinguish between binders and nonbinders which was not possible when docking to the crystal structures. These findings represent a first step toward the understanding of the binding of small-molecule XIAP-BIR2 inhibitors on a molecular level and further highlight the importance of considering protein flexibility when designing small-molecule protein-protein interaction inhibitors. © Springer-Verlag 2011.


Welsch S.J.,Priaxon AG | Welsch S.J.,Leibniz Institute of Plant Biochemistry | Kalinski C.,Priaxon AG | Umkehrer M.,Priaxon AG | And 4 more authors.
Tetrahedron Letters | Year: 2012

Indazolones are medicinally relevant targets. Herein we disclose an improved synthesis to N'-(acetamido-2-yl)-substituted indazolones with four points of diversity introduced by Ugi-[M]-amination and -amidation. The ring closure can be achieved by either conventional palladium catalysis or with a ligandless copper protocol. When α-unbranched isocyanides were employed the sole cyclization products of the copper catalyzed reactions are the hitherto undescribed 2-hydroxy-3H-3,4a,9a-triaza-fluorene-4,9-diones. © 2012 Elsevier Ltd. All rights reserved.


Welsch S.J.,Priaxon AG | Welsch S.J.,Leibniz Institute of Plant Biochemistry | Umkehrer M.,Priaxon AG | Ross G.,Priaxon AG | And 3 more authors.
Tetrahedron Letters | Year: 2011

A variety of 1,6-enynes were synthesized by an Ugi-reaction and further elaborated by a PdII/IV catalyzed oxidative cyclization to produce N-substituted 3-aza-bicyclo[3.1.0]hexan-2-ones. Different substitution patterns were tested to examine the scope and limitations of the amide tethered substrates. © 2011 Elsevier Ltd. All rights reserved.


Kalinski C.,Priaxon AG | Umkehrer M.,Priaxon AG | Weber L.,Priaxon AG | Kolb J.,Priaxon AG | And 2 more authors.
Molecular Diversity | Year: 2010

During the last decades, multicomponent chemistry has gained much attention in pharmaceutical research, especially in the context of lead finding and optimization. Here, in particular, the main advantages of multicomponent reactions (MCRs) like ease of automation and high diversity generation were utilized. In consequence of these beneficial properties, a plethora of new MCRs combined with appropriate classical reaction sequences have been published, the accessible chemical space was extended steadily. In the meantime, the desired high diversity became a challenge itself, because by now the systematic use of this huge and unmanageable space for drug discovery was limited by the lack of suitable computational tools. Therefore, this article provides an insight for the rational use of this enormous chemical space in drug discovery and generic drug synthesis. In this context, a short overview of the applied chemo informatics, necessary for the virtual screening of the biggest available chemical space, is given. Furthermore, some examples for recently developed multicomponent sequences are presented. © 2010 Springer Science+Business Media B.V.


Patent
Priaxon AG | Date: 2012-01-17

The present invention provides compounds of formula (I) or (Ia) which are ligands binding to the HDM2 protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention. Compounds of formula (I) or (Ia) can be used as therapeutics for treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimers Disease, injury from ischemic events and heart valvular degenerative disease. Moreover, compounds of formula (I) or (Ia) can be used to decrease the side effects from cytotoxic cancer agents, radiation and to treat viral infections.


Patent
Priaxon Ag | Date: 2011-06-07

The present invention relates to a method for identifying compounds comprising the steps of: (a) providing a set of compounds; (b) optionally selecting a sub-set from the set of compounds based on one or more specific compound properties; (c) generating a 3D structure of each of the compounds provided and/or selected in step (a) or (b); (d) encoding each 3D structure; (e) providing at least one known compound having at least one desired property and/or providing a target molecule; (f) encoding the 3D structure of (each of) the known compound(s) provided in step (e) and/or the active site of the target molecule provided in step (e); (g) comparing said encoded 3D structure(s) of step (d) with the encoded 3D structure(s) of step (f); and (h) selecting all compounds falling within a specified similarity range.

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