The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor.
Alessandro AgnarelliAndrea Lauer BetránAthanasios PapakyriakouViviana VellaMark SamuelsPanagiotis PapanastasopoulosChristina GiamasErika J ManciniJustin StebbingJohn SpencerChiara CilibrasiAngeliki DitsiouGeorgios GiamasPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- tyrosine kinase
- small molecule
- cancer therapy
- single cell
- epidermal growth factor receptor
- cell death
- papillary thyroid
- signaling pathway
- stem cells
- high throughput
- young adults
- squamous cell carcinoma
- transcription factor
- mass spectrometry
- case control
- bone marrow
- structural basis
- cell cycle arrest
- cell proliferation
- combination therapy
- protein protein
- squamous cell
- dna binding
- childhood cancer
- replacement therapy
- pi k akt