The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor

  • Int J Mol Sci. 2023 Jan 3;24(1):865. doi: 10.3390/ijms24010865.
Alessandro Agnarelli  1 ,  Andrea Lauer Betrán  1 ,  Athanasios Papakyriakou  2 ,  Viviana Vella  1 ,  Mark Samuels  1 ,  Panagiotis Papanastasopoulos  1 ,  Christina Giamas  1 ,  Erika J Mancini  1 ,  Justin Stebbing  3 ,  John Spencer  4 ,  Chiara Cilibrasi  1 ,  Angeliki Ditsiou  1 ,  Georgios Giamas  1
Affiliations
  • 1. Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
  • 2. Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", 15341 Athens, Greece.
  • 3. Department of Surgery and Cancer, Imperial College, London SW7 2BX, UK.
  • 4. Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
PMID: 36614307 DOI: 10.3390/ijms24010865
Abstract

Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical analyses, we identify a highly selective small molecule LMTK3 inhibitor, namely C36. Biochemical/biophysical and cellular studies revealed that C36 displays a high in vitro selectivity profile and provides notable therapeutic effect when tested in the National Cancer Institute (NCI)-60 Cancer cell line panel. We also report the binding affinity between LMTK3 and C36 as demonstrated via microscale thermophoresis (MST). In addition, C36 exhibits a mixed-type inhibition against LMTK3, consistent with the inhibitor overlapping with both the adenosine 5'-triphosphate (ATP)- and substrate-binding sites. Treatment of different breast Cancer cell lines with C36 led to decreased proliferation and increased Apoptosis, further reinforcing the prospective value of LMTK3 inhibitors for Cancer therapy.

Keywords
LMTK3; breast cancer; kinase inhibitor.
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