Community Research and Development Information Service - CORDIS

FP7

TAKTIC Report Summary

Project ID: 315746
Funded under: FP7-SME
Country: Sweden

Final Report Summary - TAKTIC (Translational Kinase Tumour Inhibitor discovery Consortium)

Executive Summary:
Within the 26 months of the TAKTIC project in total three different screening campaigns were performed for the identification of hits able to selectively inhibit the targets kinases (IKKa, IKKb and NIK). Just at the beginning of the project in WP1, we performed two campaigns, the first of which was directed against all three kinases while the second was directed against NIK and IKKb. A third screening was then performed during Period 2 and was also directed against NIK and IKKb. All screens were supported by in silico modeling and docking studies. Based on kinase selectivity and inhibition potency, the resulting hits were clustered into 15 different chemical series, which subsequently entered the initial hit-to-lead optimization process. Due to the absence of structural information from the potential complexes of the compounds with the respective proteins, techniques based on exploring structure-activity relationships (SAR) were employed in the process of hit-to-lead optimization. After initial optimization cycles, due to various reasons among which are low kinase activity and/or selectivity, IP issues as well as TAKTIC project priorities, 9 series were discarded. Of the remaining 6 series 3 were stopped in final stage of the project due to decisions made by the consortium to focus the studies on NIK kinase while the other 3 could be optimized to compounds of good-to-high potency against NIK kinase. All 9 series yielded inhibitory compounds against all 3 kinases with IC50 values in the nanomolar range, which creates a solid basis for further optimization by the involved SMEs.
The main objective of the project, delivering compound series with good inhibitory activity against IKKa, IKKb and NIK, has been achieved. In addition, after many efforts NIK has been successfully cloned, expressed and purified and crystallization experiments yielded reproducible crystals, which can be soaked with compounds.

Project Context and Objectives:
The NF-kB signalling pathway is specified by 3 main players: (1) A family of dimeric transcription factors called Nuclear Factor kB (NF-kB); (2) inhibitors of NF-kB (IkB); (3) the IkB kinase complexes (IKK), the signal integration hub for the activation of NF-kB. Binding to their respective inhibitors, IkB, normally inactivates NF-kB factors in the cytoplasm. Upstream signals from the surface or inside the cell activate the IKK complex, leading to phosphorylation of IkB, their dissociation from the complex with NF-kB, and subsequent ubiquitination and degradation. NF-kB transcription factors then accumulate in the nucleus and may bind to a class of related DNA sequences, thereby elevating or repressing the expression of hundreds of genes. Incorrect regulation of NF-kB transcription factors has been linked to cancer, inflammatory and autoimmune diseases as well as viral infections. The primary objective of this proposal is to develop highly specific inhibitory compounds targeting 3 kinases from the NF-kB pathway: IKKa, IKKb and NIK.
The TAKTIC project aims at combining accumulated specific knowledge and experience in drug discovery from 3 SMEs and academic groups to develop optimized lead candidates for at least one of the target kinases, IKKa, IKKb and NIK, as well as obtaining early lead compounds for at least one of the other kinases. Optimized lead compounds will posses the highest value and may be outlicensed or sold to other companies and may provide substantial profit for the SMEs involved, contributing to their further development.

Project Results:
Within the 26 months of the project in total three different chemical screening campaigns were performed for the identification of hits able to selectively inhibit the target kinases (IKKa, IKKb and NIK). At the beginning of the project in WP1, we performed two campaigns, the first of which was directed against all three kinases while the second was directed against NIK and IKKb. Based on kinase selectivity and inhibition potency, the resulting hits from the screenings were clustered into 15 different chemical series, which subsequently entered the initial hit-to-lead optimization process. Due to the absence of structural information from the potential complexes of the compounds with the respective proteins, techniques based on exploring structure-activity relationships (SAR) were employed in the process of hit-to-lead optimization. After initial optimization cycles, due to various reasons among which are low kinase activity and/or selectivity, IP issues as well as TAKTIC project priorities, 9 series were discarded. Compound optimisation at the initial stage of WP3 was then focused on the remaining 6 compounds. At the end of the first period of the project a decision was also made to focus the project on IKKb and NIK. The main objective became the optimization of the hits from the 6 series. Both high potency and kinase selectivity were targeted. In the beginning of the second period an additional screen targeting IKKb was run by partner ProQinase using their compound library, which contains about 25000 compounds. IC50 values were determined for IKKa, IKKb, NIK and IKKe for 121 hits. Testing against 4 kinases was done because other studies have demonstrated that inhibition of additional, especially closely related kinases, is frequently observed. Of the compounds tested 7 had IC50 values below 100 μM. However, no IC50 values below 10 µM were observed, suggesting that the inhibitory potency of the compounds is rather low. Due to the low potency and that the maximum concentration at which the compounds could be tested was 100 µM, several compounds having IC50 in the range of 100 µM essentially could not be distinguish from inactive compounds. An additional verification was performed by re-testing the compounds at 10 µM in duplicates. However, these experiments supported the notion that the number of compounds with inhibitory activity was very low.

In March 2014 the general meeting of the consortium decided to stop all efforts related to IKKb and focus on NIK. The main efforts related to the development of NIK inhibitors were focused on 3 chemical series. By the end of the project all three series produced good quality NIK inhibitors: TKT603, ~ 0.29 mkM, TKT620A and PCI11503, ~ 3 mkM, and TKT908 and 913, ~ 2 μM. Assessment of compound selectivity against a range of kinases by partner ProQinase revealed that compound TKT331 was also active against PIM1 kinase. Since crystals of PIM1 where already available, it was decided to co-crystallise TKT331 with PIM1. The information obtained from the complex helped in the optimization of this series of compounds, which eventually provided the lead compound TKT934, which showed IC50 value of 0.08 mM, in the same range as that of published NIK inhibitors. During the cycles of chemical screening and compound optimization, nano-molar inhibitor of IKKa as well as IKKb inhibitors in the low mkM range were obtained. Thus, the objectives of the project, to develop optimized lead candidates for at least one of the target kinases, and to obtain early lead compounds for at least one of the other kinases, have been completely achieved.

Potential Impact:
Our activities during the two years of the project included media coverage, presentations at international scientific conferences, newsletters, internet publications like blog entries, presentations of the project results to biotech and pharmaceutical companies at specialised partnering meetings.
A press release was distributed using a professional agent (B3C Newswire, http://www.b3cnewswire.com). The text was distributed to thousands of B3C clients, including specialized discussion groups on LinkedIn. An SME presentation prepared by the coordinator, discussing SARomics Biostructures involvement in the TAKTIC project published in MedChemWatch, the official Newsletter of the European Federation for Medicinal Chemistry, (EFMS, May 2013): (http://www.efmc.info/medchemwatch-2013-1/sme.php). The project was also presented in national (Swedish) and European media, like Life Science Sweden: (http://www.lifesciencesweden.se/biotech/lundabolag-i-spetsen-for-internationellt-kinassamarbete/) and European Biotechnology News (http://www.european-biotechnology-news.com/news/news/2013-02/six-partners-seek-kinase-drugs.html).

Among other internet media, the project was presented in SARomics company presentation at SlideShare: (slide 22-23):
http://www.slideshare.net/Salam32/sa-romics-biox20152-45568561
as well as on blog posts blog post prepared by the coordinator, published on SARomics Biostructures website (April 2013): (http://www.saromics.com/Blog/index.php?id=4296659638024109810)
and a second post summarising the first year of the project published in 2014 following the TAKTIC partners meeting in Turino: http://www.saromics.com/Blog/index.php?post=coordinating-taktic-and-surviving-the-first-year

Presentations at international scientific conferences:

Abstract presented by partner UNITO (included with the report):
XXIII International Symposium on Medicinal Chemistry, Lisbon, Portugal - September 7-11, 2014.
(http://www.ldorganisation.com/produits.php?cle_menus=1238915495)

Marco L. Lolli, Alex Ducime, Antonella Federico, Agnese Chiara Pippione, Stefano Sainas, Alessandro Barge, Katia Martina, Donatella Boschi, Elisa Lupino, Marco Piccinini, Michael Kubbutat, Christoph Schächtele, Jean Marie Contreras, Christophe Morice, Joel Sussman, Yoav Peleg, Bjorn Walse, Salam Kadaraghi (2014).
TOWARD A BIOISOSTERIC ALKAEST – APPLICATION TO THE BIOISOSTERIC MODULATION OF IMD-0354. In: Book of Abstracts. p. 234, Lisbon, Portugal, September 7-11, 2014.

Abstract by partner UNITO (included with the report):
Drug Discovery Chemistry, San Diego, USA

Lolli Marco L., Federico Antonella, Ducime Alex, Pippione Agnese, Sainas Stefano, Barge Alessandro, Martina Katia, Boschi Donatella, Lupino Elisa, Piccinini Marco, Kubbutat Michael, Contreras Jean Marie, Morice Christophe, Sussman Joel, Peleg Yoav, Walse Bjorn, Al-Kadaraghi Salam (2014).
Towards a Bioisosteric Alkaest: application to the bioisosteric modulation of IMD-0354. In: Book of Abstracts. p. 100, San Diego, USA, April 23-25.
Poster 1 (included, presented by partner UNITO at a meeting in Lisbon):
Towards a Bioisosteric Alkahest: Application to the bioisosteric modulation of IMD-0354.
The poster can be accessed at SARomics website using the link: http://www.saromics.com/resources/Experimental/EMD0354-Story-Poster-EFMC-20140904-Lolli.pdf

Poster 2 (included, presented by partner UNITO at a meeting in San Diego):
Towards a Bioisosteric Alkahest: Application to the bioisosteric modulation of IMD-0354

The poster can be accessed at SARomics website using the link:
http://www.saromics.com/resources/Experimental/Poster-CHi-conference-17042014-final.pdf

Poster 3 : Structure-based discovery of novel NIK inhibitors
Presented at RICT 2014 by partner Prestwick, Rouen, Normandy, France - July 2-4, 2014.
http://www.ldorganisation.com/v2/page/rict_2014_international_conference_medicinal_chemistry/products.html

The poster can be accessed at SARomics website using the link:
http://www.saromics.com/resources/Experimental/20140616-TAKTIC_poster_RICT-EFMC_final.pdf

Poster 4: Comparison of Hit Discovery approaches. CASE STUDY: NIK inhibitors
Presented at EFMC-ISMC 2014 by partner Prestwick:
http://www.ldorganisation.com/produits.php?cle_menus=1238915495

Will also be presented at Drug Discovery Chemistry (San Diego, April 21-23, 2015) : http://www.drugdiscoverychemistry.com/

The poster can be accessed at SARomics website using the link:
http://www.saromics.com/resources/Experimental/20140808_PRESTWICK_poster_Hit-discovery.pdf

All poster mentioned above have been added to the list of publications at SARomics website:
http://www.saromics.com/About/About/publications.html

Presentations at partnering meetings:

BIO-Europe 2013, Vienna, Austria, November 4-6, 2013
BIO-Europe Spring 2014, Turin, Italy, March 10-12, 2014
BIO International 2014, San Diego, USA, June 24-26, 2014
Nordic Life Science Days, Stockholm, Sweden, September 8-9, 2014
Bio Japan 2014, Yokohama, Japan, October 15-17, 2014
BIO-Europe 2014, Frankfurt, Germany, November 3-5, 2014

At these partnering meetings SARomics internal projects were presented to companies and investors for future out-licensing or investments. Most partnering meetings have been held with representatives from the big pharma in-licensing teams. TAKTIC slides were part of these presentations. Specifically at the BIO-Europe 2015 meeting in Frankfurt the TAKTIC project had a special focus and recent results were presented to various interested in-licensing teams from a number of big pharma companies.

In addition, at the Bio Japan meeting in Yokohama a specific Scandinavian session was organized (October 16) and SARomics held a 7 min presentation to a large audience (see picture below). One slide in the presentation was about TAKTIC. Furthermore, the day before the Bio Japan meeting SARomics also made a company presentation at a matchmaking event at the Danish embassy in Tokyo (October 14). Also here a slide about TAKTIC was presented to an audience with several representatives from Japanese big pharma companies.

The TAKTIC project has also been presented at various site visits to pharma and biotech companies during the period. Some examples include Johnson and Johnson in San Diego, ONO Pharma in Osaka, Medivir in Stockholm and BiogenIdec in Boston. The TAKTIC presentation can be found at (slides 22 & 23): http://www.saromics.com/resources/Flyers/SARomicsBioX2015-2.pdf

Thus, it may be concluded that the project has received appropriate coverage in the media, to the extent which the confidentiality of the project requires. A publication in a major medicinal chemistry journal will contribute to the image of the project and will help in possible applications for additional funds for the finalisation of the TAKTIC lead compound and its introduction into the market.

List of Websites:
Due to the confidential character of the project, no specific website was developed. However, SARomics website (www.saromics.com) has been used for promoting the project to a wider audience, for publishing a press release, several blog entries as well as posters, which were presented at conferences. Other partners websites were also used for the same purpose.

Related information

Contact

Salam Al-Karadaghi, (Director Business Development)
Tel.: +46 2224512
E-mail
Record Number: 186834 / Last updated on: 2016-07-13