ijms-24-00865 (1).pdf (4.76 MB)
Download fileThe inhibitory properties of a novel, selective LMTK3 kinase inhibitor
journal contribution
posted on 2023-06-10, 05:57 authored by Alessandro AgnarelliAlessandro Agnarelli, Andrea Lauer BetranAndrea Lauer Betran, Athanasios Papakyriakou, Viviana Vella, Mark SamuelsMark Samuels, Panagiotis Papanastasopoulos, Christina Giamas, Erika J Mancini, Justin Stebbing, John SpencerJohn Spencer, Chiara Cilibrasi, Angeliki Ditsiou, Georgios GiamasGeorgios GiamasRecently, 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.
History
Publication status
- Published
File Version
- Published version
Journal
International Journal of Molecular SciencesISSN
1661-6596Publisher
MDPI AGExternal DOI
Issue
1Volume
24Page range
e865 1-15Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes