The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor

Int J Mol Sci. 2023 Jan 3;24(1):865. 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.

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Prospective Studies
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Serine-Threonine Kinases* / antagonists & inhibitors

Substances

  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • LMTK3 protein, human