(667.15) Selective targeting of the inactive state of hematopoietic cell kinase (Hck) with a stable curcumin derivative

Poster Board Number: A340

Manas Chakraborty (Indian Institute of Science Education and Research Kolkata), Sudipta Bhattacharyya (Indian Institute of Science Education and Research Kolkata), Souryadip Roy (Indian Institute Of Science Education and Research Kolkata), Indira Bhattacharya (University of Maryland), Rahul Das (Indian Institute of Science Education and Research Kolkata), Arindam Mukherjee (Indian Institute Of Science Education and Research Kolkata)

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 (Treon et al., Blood, 2020). Hck inhibitors are also well known for their regulatory role in various malignancies and autoimmune diseases (Ashleigh et al., Oncotarget,2015). Previous report shows that binding of curcumin to active conformation of DYRK2 at sub nanomolar range makes it an excellent DYRK-2 inhibitor(Banerjee et al., PNAS,2018) , but curcumins fate is tainted by its instability in the cellular environment and its nonspecific binding nature(Kathryn et al., J. Med. Chem.,2017). Besides, the planar symmetry makes curcumin less druggable toward asymmetric binding pockets such as kinases (Knight et al., Chem. Biol. 2005). small molecules targeting the inactive states of a kinase are desirable to reduce promiscuity (Hanson et al., Chembiol., 2019). 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 which binds specifically to the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous.

Moreover, the lead compound showed no inhibitory effect on two other kinases (DYRK2 and Abl) which can be explained by difference in p-loop dynamics between Abl and src family kinases. 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.

The work presented in this article is extramurally funded by Science and Engineering Research Board(SERB), Government of India vide project no. EMR/2107/002324, ECR/2015/000142 and DBT (Department of Biotechnology) Ramalingaswami Fellowship BT/RFF/Re-entry/14/2014l to R. D. We thank Dr Arnab Gupta for helping us with the confocal microscopy, a facility funded by DBT Welcome Trust to A. G. Authors S. B. and M. P. C. thank CSIR (Council of Scientific and Industrial Research) and S. R. thanks INSPIRE for their respective research fellowships. We are thankful to IISER-K for the financial support.



Table of Contents image