Your browser doesn't support javascript.
Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative.
Chakraborty, Manas Pratim; Bhattacharyya, Sudipta; Roy, Souryadip; Bhattacharya, Indira; Das, Rahul; Mukherjee, Arindam.
  • Chakraborty MP; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India.
  • Bhattacharyya S; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India.
  • Roy S; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India.
  • Bhattacharya I; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India.
  • Das R; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India; Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India. Electronic address: rahul.das@iiser
  • Mukherjee A; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India; Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur, India. Electronic address: a.mukherjee@iiser
J Biol Chem ; 296: 100449, 2021.
Article in English | MEDLINE | ID: covidwho-1091794
ABSTRACT
Hck, a Src family nonreceptor 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 signaling 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 remodeling its target affinity and cellular stability.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Drug Design / Curcumin / Protein Kinase Inhibitors / Epithelial Cells / Proto-Oncogene Proteins c-hck Language: English Journal: J Biol Chem Year: 2021 Document Type: Article Affiliation country: J.jbc.2021.100449

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Drug Design / Curcumin / Protein Kinase Inhibitors / Epithelial Cells / Proto-Oncogene Proteins c-hck Language: English Journal: J Biol Chem Year: 2021 Document Type: Article Affiliation country: J.jbc.2021.100449