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Enzyme Inhibitors   |   Photopharmacology   |   Molecular Imaging Probes

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Enzyme Inhibitors (EI)

We are developing enzyme inhibitors to be used as tool compounds as well as potential lead compounds for drug development.

Current targets include:

Rearranged during transfection (RET), a transmembrane tyrosine-protein kinase

Collaborators include Andréasson, Lundbäck and CBCS.

Design and Development of Photoswitchable DFG-Out RET Kinase Inhibitors. Yongjin Xu, Chunxia Gao, Måns Andreasson, Liliana Håversen, Marta Carrasco,  Cassandra Fleming, Thomas Lundbäck,  Joakim Andréasson and Morten Grøtli. Eur. J. Med. Chem. 2022, 234, 114226.

Design and Development of a Photoswitchable DFG-Out Kinase Inhibitor. Yongjin Xu, Chunxia Gao, Liliana Håversen, Thomas Lundbäck, Joakim Andréasson and Morten Grøtli. Chem. Commun. 2021, 57, 10043.

 

Lymphocyte-specific protein tyrosine kinase (LCK), a non-receptor tyrosine-protein kinase

Collaborators include Andréasson, Lundbäck and CBCS.

A Fluorescent LCK Inhibitor that Exhibits Diagnostic Changes in Emission Upon Binding the Kinase Enzyme, Cassandra Lee Fleming, Patrick A Sandoz, Tord Inghardt, Björn Önfelt, Morten Grøtli, Joakim Andreasson. Angew. Chem. Int. Ed.,  2019, 58, 15000 –15004.

 

Pyruvate kinase liver isoform (PKL)

Collaborators include Mardinoglu, Boren and Hyvonen.

Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase. Amalyn Nain-Perez, Anders Foller Füchtbauer, Liliana Håversen, Aleksei Lulla, Chunxia Gao, Josipa Matic, Leticia Monjas, Alexandra Rodríguez, Paul Brear, Woonghee Kim, Marko Hyvönen, Jan Borén, Adil Mardinoglu, Mathias Uhlen and Morten Grøtli. Eur. J. Med. Chem. 2022, 234, 114270.

Network analyses identify liver-specific targets for treating liver diseases, Sunjae Lee, Cheng  Zhang , Zhengtao Liu, Martina Klevstig, Bani Mukhopadhyay, Mattias Bergentall, Resat Cinar, Marcus Ståhlman, Natasha Sikanic, Joshua K Park, Sumit Deshmukh, Azadeh M Harzandi, Tim Kuijpers, Morten Grøtli, Simon J Elsässer, Brian D Piening, Michael Snyder, Ulf Smith, Jens Nielsen, Fredrik Bäckhed, George Kunos, Mathias Uhlen, Jan Boren and  Adil Mardinoglu. Mol. Sys. Biol. 2017, 13, 938.

 

N-myristoyltransferase (NMT), a glycylpeptide N-tetradecanoyltransferase

Collaborators include Staker,  Kaushansky and Sunnerhagen. 

 

Aminoacyl-tRNA synthetases (AARSs), a group of cytoplasmic enzymes that catalyse the binding of tRNA to their respective amino acids

Collaborators include Torres-Larios.

Structural Insights into the Polyphyletic Origins of Glycyl tRNA Synthetases, Marco Igor Valencia-Sánchez, Annia Rodríguez-Hernández, Ruben Ferreira, Hugo Aníbal Santamaría-Suárez, Marcelino Arciniega-Castro, Anne-Catherine Dock-Bregeon, Dino Moras, Brice Beinsteiner, Haydyn Mertens, Dmitri Svergun, Luis Brieba de Castro, Morten Grøtli, Alfredo Torres-Larios, J. Biol. Chem. 2016, 291, 14430–14446.

 

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase.

Collaborators include Malmerberg and Janic.

 

 

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Photopharmacology (PP)

Lack of probe selectivity is a recurrent problem in pharmacological treatments and is caused by the inability to control the activity of the probe in time and space. We are addressing this issue by incorporating photo-responsive groups (photoswitches and photolabile protecting groups) into the molecular structure of kinase inhibitors. These inhibitors allow for the use of light to externally control activity, which can be delivered with very high spatiotemporal precision.

Collaborators include: Andréasson and König.

A Fluorescent LCK Inhibitor that Exhibits Diagnostic Changes in Emission Upon Binding the Kinase Enzyme, Cassandra Lee Fleming, Patrick A Sandoz, Tord Inghardt, Björn Önfelt, Morten Grøtli, Joakim Andreasson. Angew. Chem. Int. Ed.,  2019, 58, 15000 –15004.

Synthesis and Photophysical Characterization of Azoheteroarenes,  Yongjin Xu, Chunxia Gao, Joakim Andréasson, Morten Grøtli. Org. Lett. 2018, 20, 4875–4879.

 

 

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Molecular Imaging Probes (MIP)

Molecular imaging probes are agents used to visualize, characterize and quantify biological processes in living systems.

Fluorescent nucleic acid base analogs (FBAs) are structural analogs of the standard DNA/RNA bases, which are highly fluorescent, and form Watson-Crick hydrogen bonds with complementary bases. We are developing FBAs for studying structure and dynamics of nucleic acids.

Collaborators include: Wilhelmsson and Lemurell.

Synthesis, oligonucleotide incorporation and fluorescence properties of a bicyclic thymine analogue in DNA, Christopher P. Lawson, Anders F. Füchtbauer, Moa S. Wranne, Tristan Giraud, Thomas Floyd, Blaise Dumat, Nicolai Krog Andersen, Afaf El-Sagheer, Tom Brown, Henrik Gradén, Marcus Wilhelmsson, Morten Grøtli. Sci. Rep. 2018, 8, 13970; doi: 10.1038/s41598-018-31897-2

Pentacyclic adenine: a versatile and exceptionally bright fluorescent DNA base analog, Mattias Bood, Anders F. Füchtbauer, Moa S. Wranne, Jong Jin Ro, Sangamesh Sarangamath, Afaf H. El-Sagheer, Déborah L. M. Rupert, Rachel Fisher, Steven W. Magennis, Anita C. Jones, Fredrik Höök, Tom Brown, Byeang Hyean Kim, Anders Dahlén, L. Marcus Wilhelmsson and Morten Grøtli. Chem. Sci., 2018, 9, 3494 – 3502.

 

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Multiphoton microscopy is a benchmark tool in biomedical research, used for the fluorescence imaging in cellular environments. This has important implications for disease diagnosis and the monitoring of therapy response.

In conventional two-photon microscopy the fluorescence intensity of the employed molecular probe is proportional to the square of the excitation light intensity, implying that the fluorescence from the sample is confined around the focal point, yielding good spatial resolution. The spatial resolution can be dramatically improved by drawing on higher-order processes such as four photon absorption.

As a part of an EU funded project entitled Breaking the Resolution Limit in Two-Photon Microscopy Using Negative Photochromism (4for2), we are developing molecules that combine two mechanistically entangled two-photon processes for the generation of a fluorescence output. This is possible by merging two-photon absorption, two-photon FRET-induced photoisomerization, and negative photochromism.

Collaborators include Andréasson, Pischel and Hofkens.