1. Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative
- Author
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Sudipta Bhattacharyya, Indira Bhattacharya, Manas Pratim Chakraborty, Souryadip Roy, Rahul Das, and Arindam Mukherjee
- Subjects
0301 basic medicine ,Gene Expression ,Biochemistry ,Mice ,chemistry.chemical_compound ,Drug Stability ,enzyme kinetics ,Src family kinase ,Cloning, Molecular ,Proto-Oncogene Proteins c-abl ,Research Articles ,Hck inhibitor ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,ABL ,Kinase ,Protein-Tyrosine Kinases ,Recombinant Proteins ,Cell biology ,src-Family Kinases ,Proto-Oncogene Proteins c-hck ,cell-signalling ,Signal transduction ,HT29 Cells ,Tyrosine kinase ,Biotechnology ,Proto-oncogene tyrosine-protein kinase Src ,Cell signaling ,Curcumin ,Genetic Vectors ,Protein Serine-Threonine Kinases ,Structure-Activity Relationship ,03 medical and health sciences ,Cell Line, Tumor ,Genetics ,Escherichia coli ,Animals ,Humans ,Protein Kinase Inhibitors ,Molecular Biology ,030102 biochemistry & molecular biology ,Epithelial Cells ,Cell Biology ,kinase inhibition ,HEK293 Cells ,RAW 264.7 Cells ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,curcumin derivative ,Drug Design - Abstract
Hck, a Src family non-receptor tyrosine kinase (SFK), has recently been established as an attractive pharmacological target to improve pulmonary function in COVID-19 patients. Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases. Curcumin has been previously identified as an excellent DYRK-2 inhibitor, but curcumin's fate is tainted by its instability in the cellular environment. Besides, small molecules targeting the inactive states of a kinase are desirable to reduce promiscuity. Here, we show that functionalization of the 4-arylidene position of the fluorescent curcumin scaffold with an aryl nitrogen mustard provides a stable Hck inhibitor (Kd = 50 ± 10 nM). The mustard curcumin derivative preferentially interacts with the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous. Moreover, the lead compound showed no inhibitory effect on three other kinases (DYRK2, Src and Abl). We demonstrate that the cytotoxicity may be mediated via inhibition of the SFK signalling pathway in triple-negative breast cancer and murine macrophage cells. Our data suggest that curcumin is a modifiable fluorescent scaffold to develop selective kinase inhibitors by remodelling its target affinity and cellular stability.
- Published
- 2021
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