Since the discovery of glycogen phosphorylase in the 1960s, kinases are subject of ongoing research. Sequencing of the humane genome even revealed that about 2% thereof are encoding for protein kinases. They play crucial roles in various cellular functions ranging from metabolism over cell cycle regulation to differentiation and apoptosis.

Protein kinases are enzymes that phosphorylate proteins by transferring the chemically labile terminal γ-phosphate group of adenosine triphosphate (ATP) to the hydroxy group of serine, threonine, or tyrosine residues. Thus, they are also called phosphotransferases. This process leads to a change in the protein’s geometrical structure resulting in functional changes. This mechanism is used to induce a signal transduction cascade from the cell membrane to the interior of the cell. In living cells, such phosphorylation processes are constantly occurring, e.g. as part of cell proliferation, differentiation, and apoptosis, and are highly regulated.

Typically, aberrations and dysfunction are the origin of various diseases including cancer as well as neurological, metabolic, and infectious disorders. Thus, protein kinases are one of the most attractive subjects for therapeutic regulation amounting to around 20-30 % of the drug discovery efforts worldwide.

In 2001, the first kinase inhibitor Imatinib (Gleevec) was approved by the Food and Drug Administration (FDA). This tyrosine kinase inhibitor blocks the kinase receptor from binding to ATP thus preventing phosphorylation, which might promote cell division and cancer development.

Recently, controversial reports highlighted Imatinib in the context of Covid-19. The pandemic SARS-CoV-2 counts roughly 41 million recorded cases as by October 22^nd, 2020 (www.WHO.org). To accelerate the search for antivirals and vaccines, drugs which are already approved by the FDA for human use are repurposed for the treatment of Covid-19 as their drug profiles are already well investigated. In one study, Imatinib is suggested as potential hit against SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV) as it might inhibit spike-mediated fusion of coronaviruses with cellular membranes, thus blocking entry. However, the anti-SARS-CoV-2 efficacy of Imatinib in a standard viral replication assay has not been demonstrated.

Besides Imatinib, Iris Biotech provides alkylamine linked analogues of other well-known kinase inhibitors including Bosutinib, Gefitinib, PP58, Staurosporine, Sunitinib and many more, which can easily be conjugated to further biomolecules, e.g. for the generation of ADCs, PROTACs and others.

References:

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• Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. P. Schöffski, H. Dumez, P. Clement, A. Hoeben, H. Prenen, P. Wolter, S. Joniau, T. Roskams, H. Van Poppel; Ann. Oncol. 2006; 17: 1185-1196. https://doi.org/10.1093/annonc/mdj133.
• Tyrosine Kinase Inhibitors – A Review on Pharmacology, Metabolism and Side Effects. J. T. Hartmann, M. Haap, H.-G. Kopp, and H.-P. Lipp; Curr Drug Metab. 2009; 10: 470-481. https://doi.org/10.2174/138920009788897975.
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• Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. C. Pottier, M. Fresnais, M. Gilon, G. Jérusalem, R. Longuespée, and N. E. Sounni; Cancers 2020; 12: 731. https://doi.org/10.3390/cancers12030731.
• Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. R. Roskoski Jr.; Pharmacol. 2020; 152: 104609. https://doi.org/10.1016/j.phrs.2019.104609
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• Kinase inhibitors: the road ahead. F. M. Ferguson, N. S. Gray; Nat. Rev. Drug Discov. 2018; 17: 353-377. https://doi.org/10.1038/nrd.2018.21.
• Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo. S. Weston, C. M. Coleman, J. M. Sisk, R. Haupt, J. Logue, K. Matthews, M. B. Frieman; bioRxiv 2020. https://doi.org/10.1101/2020.03.25.008482.
• Imatinib is not a potent anti-SARS-CoV-2 drug. H. Zhao, M. Mendenhall, M. W. Deininger; Springer Nature 2020. https://doi.org/10.1038/s41375-020-01045-9.