Enzyme Inhibitors | Photopharmacology | Molecular Imaging Probes
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) is a receptor tyrosine kinase that plays a crucial role in the development of the nervous system and kidneys. It is also involved in various cancers and developmental disorders. Despite extensive research, there are still several knowledge gaps regarding RET kinase. These gaps can be broadly categorized into biological, pathological, and therapeutic aspects.
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) is a member of the Src family of tyrosine kinases and plays a crucial role in T cell development and activation. Despite extensive research, numerous knowledge gaps persist in our understanding of LCK kinase.
Collaborators include Andréasson, Lundbäck and CBCS.
All-Photonic Kinase Inhibitors: Light-Controlled Release-and-Report Inhibition. Cassandra L. Fleming, Carlos Benitez-Martin, Elin Bernson, Yongjin Xu, Linnea Kristenson, Tord Inghardt, Thomas Lundbäck, Fredrik B. Thorén, Morten Grøtli and Joakim Andréasson. Chem. Sci. 2024, 15, 6897.
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) is a key enzyme in glycolysis, catalysing the conversion of phosphoenolpyruvate (PEP) to pyruvate with the production of ATP. The liver isoform of pyruvate kinase (PKL) plays a crucial role in regulating glucose metabolism in the liver. 
Collaborators include Mardinoglu, Boren and Hyvonen.
Sulfone-based human liver pyruvate kinase inhibitors – design, synthesis and in vitro bioactivity. Josipa Matića, Fady Akladiosa, Umberto Maria Battistia, Liliana Håversen, Amalyn Nain-Pereza, Anders Foller Füchtbauera, Woonghee Kim, Leticia Monjasa, Alexandra Rodriguez Riveroa, Jan Borén, Adil Mardinoglub, Mathias Uhlen, and Morten Grøtli. Eur. J. Med. Chem. 2024, 269,116306.
Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators. Amalyn Nain-Perez, Oscar Nilsson, Aleksei Lulla, Liliana Håversen, Paul Brear, Sara Liljenberg, Marko Hyvönen, Jan Borén and Morten Grøtli. Eur. J. Med. Chem. 2023, 250, 115177.
N-myristoyltransferase (NMT) is an enzyme that catalyzes the covalent attachment of myristic acid, a 14-carbon saturated fatty acid, to the N-terminal glycine residue of proteins. This modification is essential for the proper functioning of various proteins, including those involved in signal transduction, membrane targeting, and protein-protein interactions. NMT has emerged as a promising target for antimalarial drug development due to its crucial role in the survival and pathogenicity of Plasmodium spp., the parasites responsible for malaria.
Collaborators include Staker, Kaushansky and Sunnerhagen.
Exploring subsite selectivity within Plasmodium vivax N-myristoyltransferase using pyrazole-derived inhibitors. Diego Rodríguez-Hernández, Michael K. Fenwick, Rachael Zigweid, Banumathi Sankaran, Peter J. Myler, Per Sunnerhagen, Alexis Kaushansky, Bart L. Staker and Morten Grøtli. J. Med. Chem. 2024, 67, 7312.
Identification of potent and Selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts. Diego Rodríguez-Hernández, Kamalakannan Vijayan, Rachael Zigweid, Michael K. Fenwick, Banumathi Sankaran, Wanlapa Roobsoong, Jetsumon Sattabongkot, Elizabeth K.K. Glennon, Peter J. Myler, Per Sunnerhagen, Bart L. Staker, Alexis Kaushansky, Morten Grøtli. Nat. Commun. 2023, 14, 5408.
Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase.
Collaborators include Malmerberg and Janic.
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.
All-Photonic Kinase Inhibitors: Light-Controlled Release-and-Report Inhibition. Cassandra L. Fleming, Carlos Benitez-Martin, Elin Bernson, Yongjin Xu, Linnea Kristenson, Tord Inghardt, Thomas Lundbäck, Fredrik B. Thorén, Morten Grøtli and Joakim Andréasson. Chem. Sci. 2024, 15, 6897.
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.
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.
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.