2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib

Background Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds. Results We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral “multi-targeted” small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action. Conclusion In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib

Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

Although both Mcl-1 and Bcl-xL keep proapoptotic Bak in check, it is the loss of Mcl-1 that sensitizes cells to death receptor–mediated apoptosis

Bedeutung des p53-Signalwegs für Apoptoseaktivierung und Zellzyklusarrestregulation durch das p14 ARF Tumorsuppressorgen

BH3-only Proteine, eine pro-apoptotische Untergruppe der Bcl-2 Proteinfamilie, sind zentrale Mediatoren von apoptotischen Signalen durch die Regulierung intrinsischer Apoptose-signalwege. Unsere Arbeitsgruppe hat vor kurzem gezeigt, dass Apoptose, die durch den p14ARF Tumorsuppressor induziert wird über die p53-abhängige Aktivierung des BH3-only Proteins Puma/Bbc3 vermittelt wird. Interessanterweise induziert p14ARF aber auch in p53 defizienten Zellen Zellzyklusarrest und Apoptose. Die dahinterliegenden Signalwege sind jedoch nicht bekannt. In dieser Arbeit berichten wir, dass das BH3-only Protein Bmf (Bcl-2 modifying factor) beim p14ARF-induzierten Zelltod in p53 defizienten Zellen eine wichtige Rolle spielt. Expression von p14ARF führt zu einer Induktion der PERK Kinase, daran anschließender Phosphorylierung von eIF2α sowie Aktivierung der stromabwärts liegenden Transkriptionsfaktoren ATF4 und CHOP. Diese Signalkaskade ist normalerweise Teil einer zellulären Antwort auf fehl- oder ungefaltete Proteine im Endoplasmatischen Retikulum (ER), der sogenannten ‘unfolded protein response’ (UPR), die zum einen durch verminderte Translationsinitiation und Hochregulierung von Chaperonen die Menge der fehlgefalteten Proteine reduzieren soll. Allerdings induziert p14ARF keinen ER Stress, sondern den PERK‒CHOP Signalweg. Die Transkriptionsfaktoren ATF4 und CHOP binden direkt in der Promotorregion von bmf und sind für dessen transkriptionelle Regulation verantwortlich. Unsere Daten zeigen, dass der PERK‒eIF2α‒ATF4‒CHOP Signalweg eine wesentliche Rolle bei der Induktion von Apoptose durch p14ARF spielt. Dieser Weg könnte ein Sicherungsmechanismus sein, der es den Zellen auch nach Verlust von p53 erlaubt Apoptose einzuleiten, nachdem p14ARF durch Onkogene hochreguliert wurde.BH3-only proteins, a pro-apoptotic subgroup of the Bcl-2 family of proteins, are central mediators of apoptosis signals by regulating the intrinsic apoptosis pathway. We have recently shown, that apoptosis triggered by the p14ARF tumour suppressor protein is mediated by the p53-dependent activation of the BH3-only protein Puma/Bbc3. Nevertheless, expression of p14ARF in p53-family deficient cells is capable of inducing both cell cycle arrest and apoptosis, but the signalling pathways initiated remain elusive. Here, we report that the BH3-only protein Bmf (Bcl-2 modifying factor) is involved in cell death in p53-deficient cells triggered by p14ARF. Expression of p14ARF leads to the induction of the PERK kinase, subsequent phosphorylation of eIF2α and activation of transcription factors ATF4 and CHOP. This signalling cascade is usually part of the ‘unfolded protein response’ (UPR), which is activated upon ER stress to reduce the amount of misfolded proteins by reduction of global protein translation initiation and upregulation of chaperones. Of note, p14ARF does not induce ER stress but activates the PERK‒CHOP pathway. ATF4 and CHOP transcription factors directly bind to the promotor region of bmf and induce its transcription. These data suggest that the PERK‒eIF2α‒ATF4‒CHOP signalling pathway may play a substantial role in mediating p14ARF-triggered apoptosis. This pathway could play the role of a ‘fail-safe’ mechanism that allows cells, even after loss of p53, to undergo apoptosis induced by upregulation of p14ARF by oncogenes

How Service Ideas Are Implemented : Ways of Framing and Addressing Service Transformation

As a field in practice and academia, service design is moving out of its formative phase. In service design research, the realisation of service transformation from idea to service practice and the ways that design(ers) can contribute to this process are topics that are not well understood yet. The work presented in this thesis contributes to improving this understanding. A programmatic design research approach was used to explore service transformation. This resulted in the formulation of two ways of framing and addressing the topic: type 1 service transformation, which frames the realisation of service transformation in terms of assembling a service delivery system, and type 2 service transformation, which views the realisation of service transformation as enabling value co-creating relationships between service actors. Type 1 service transformation builds on the assimilation perspective on service innovation where service transformation is realised by implementing service concepts. Service Design contributes to this by facilitating the development of desirable service experiences. Trained designers can apply implementation strategies and support the handover of service design projects to contribute to the realisation of type 1 service transformation by. Design for manufacture and assembly (DFMA) is a generative construct for addressing type 1 service transformation. DFMA is central to the program implementation during design, which was used to explore type 1 service transformation. Type 2 service transformation builds on the synthesis perspective on service innovation, which adopts a service-dominant logic. Service transformation is the shaping of value co-creating relationships between service actors and is realised by enabling service actors to enact roles that make the envisioned value co-creating relationships possible. Designing contributes by helping service developers to improve their understanding of value co-creating relationships and the way that realising service transformation is expected to affect those relations. Trained designers contribute by supporting this inquiry. The concept of roles, including Role Theory vocabulary, is a generative construct for addressing type 2 service transformation and is central to the program enabling enactment, which is suggested for the study of type 2 service transformation. The main contribution of this thesis is the articulation of these two perspectives on service transformation. The articulation of these two framings helps service developers and researchers in their efforts to study and work on the realisation of service transformation

Jamming to Direct Technology Development : An Analysis of Two Technology Jams

When technology is taken as the starting point for the development of new products and services, there is a risk for so-called technology-push innovations. Instead, the technology-driven perspective could be complemented with a design driven perspective (Verganti, 2009), in order to help create a better balance in desirability, feasibility and viability (Brown 2009). However, design driven innovation processes usually are time-intensive. With the development of Technology Jams we aim to speed up the design driven process, while preserving its other characteristics.. These Technology Jams are inspired on musical jams and design jams, where people from different backgrounds explore ideas together in a hands-on way. However, technology Jams take a specific technology and a target context as a starting point for ideation of new products and services. Rapid prototypes are used to give shape to these ideas in order to explore and improve them. In this paper we introduce the concept of Technology Jams. Furthermore, we describe two Technology Jams that we have organised. We discuss how their respective theme, setup and provided working material affected the process and outcome of the Technology Jams. We conclude by pointing out directions for possible future development and additional research in order to iteratively improve the concept of Technology Jams.Printed Electronics Meets Mobil

Views on implementation and how they could be used in service design

Although service designers have proven their abilities in the fuzzy front end of service development, their skills regarding implementation have been criticised and many service designs are not implemented successfully. So far, there has been little discussion concerning service implementation in service design research and there is potential for further development of this aspect of the design of services. This paper intends to contribute to this development by presenting different views on implementation from fields that are related to service design, such as product and interaction design. These fields mostly see implementation as the delivery of generic resources and process models, whereas service implementation (also) involves development and change of the (service) organisation as well as adaptation in use of resources and service processes models. Still, if discussions on implementation in these related fields are translated to a service context, they can provide inspiration for (future research on) service implementation

Evolutions of service actor roles towards future service

Realising new ways of value co-creation involves changes in the roles of actors in a service system. Role Theory and its concepts have been used in service research to articulate dynamics in service actor roles in existing value co-creation situations, but they are not applied to evaluate roles in future situations of service. Several methods exist in (service) design that can be used to describe existing roles in service systems and to suggest possible futures based on these descriptions, but describing roles in these futures in a structured way is not a part of these methods. Structured ways to describe service actor roles in envisioned services are thus lacking, which makes it difficult to assess the feasibility of the evolution from contemporary service actor roles towards realising services. In this paper, we suggest how Role Theory and theatre-inspired methods in design can complement one-another to fill this gap. We use interview data from the evaluation of an envisioned service scenario to show how Role Theory can be used as an analytical perspective to describe roles in this envisioned service. Finally, we suggest possible directions for future research

Implementation during design : Developing understanding about service realisation before implementation

Design has been mentioned as potential support in the shift from a valuein-exchange to a value-in-use perspective that is part of servitization. However, thesediscussions pay little attention to the role of design(ers) for implementing 1) thechange in perspective of the organisation and 2) specific (product) service systems,which are both required for successful servitization.We argue that implementation as a concept needs to be part of service designprocesses in order to timely articulate how to implement new services, and whatresources need to be shaped in service system(s) involved for successful value cocreation.We analyse a workshop in a technology-dominant service developmentproject and show that using a service (process) perspective and concrete cases couldbe a way to integrate conversations about implementation in the design phase of PSSand service development. For technology-dominant services specifically, this canuncover factors for successful integration of technology and service.Funding agencies: Vinnova program for Strategic Vehicle Research and Innovation (FFI); project DiaGuide2 [2014-03942]</p

Roles of in-house designers towards service implementation

In this paper, we study roles that in-house service designs take towards service implementation. We frame implementation from a service-dominant logic and service systems perspective as shaping service system resources (people, language, organisation technology) for resource exchange and integration (i.e. value co-creation). We analyse interviews with nine in-house service designers and show how in-house designers work with shaping the four service system resource types. We discuss implications for in-house designers and (their) managers. We reflect on using service-dominant logic and service systems as a lens for analysing in-house designers’ efforts related to service implementation. We make suggestions for future research