Task 5 : In vitro and in vivo evaluation of compounds

There is three objectives of this task

• First to evaluate the inhibitory properties of the compounds design in task 3 regarding cell toxicity, proliferation and migration. Their ability to induce apoptosis will be also tested. Non-toxic compounds will be tested on their capacity to reduce cell migration and only toxic compounds non acting on conventional apoptosis pathways will be retained. Indeed, we believe that resistance to conventional pro-apoptotic stimuli could be reversed by concurrent treatment with The retains compounds will be tested in their ability to modulate calcium signaling and cell migration by acting on SK3 channel, Orai, TRPC1/4 channels and its regulators STIM.
• Second to evaluate the toxicity/tolerance and efficacy of compounds selected on ImPACcell platform on in vivo pre-clinical models.The selected leads will then be tested in vivo alone or with conventional chemotherapy or targeted therapy on primary tumor and metastasis development.
• Third to evaluate of STIM1/Orai1 inhibitors obtained by virtual screening.

We plan to test STIM1/Orai1 inhibitors predicted in silico by virtual screening by Dr W Brooks and W Guida (University of South Florida, USA) using NFAT2-GFP transfected human Jok -1 B cells in order to evaluate STIM1/Orai activation.