Molecular design of fluorescence probes for cell bio-imaging from a new “Store Operated Calcium Entry/Orai1” inhibitor of pancreatic cancer: the delikine DAD3.473.

Calcium channel Orai1 is currently considered as an emerging and relevant target in cancer due to its indirect contribution, particularly in cell migration/invasion and metastatic spread. Therefore, the calcium channel Orai1 represents a promising therapeutic lead and accessibility to a selective inhibitor is a challenge for preventive treatment of metastases. During a Structure Activity Relationship study around SKF-96365 (a molecule used as reference for measuring calcium influx since 1991), delikine molecules were identified as a new family of selective inhibitors targeting SOCE calcium influx controlled by the membrane protein Orai1. Thus, the delikine DAD3.4733 was identified and patented in 2020 as an active "hit" on pancreatic carcinoma cells PANC1 and on breast carcinoma cells MDA-H321 during the RSA study. To date, the mechanism of action of industrial SOCE/Orai1 inhibitors (GSK-96365 and CM4620) in clinical studies, is not or is poorly controlled. In this context and to try to build proof of concept around this new SOCE/Orai1 inhibitor, we decided to develop fluorescence probes derived from the delikine DAD3.473. To achieve this objective, we opted for the use of a short linker (3 or 4 carbon atoms) so as not to disturb the intrinsic character of this SOCE inhibitor, and to graft it onto the West, East or North of this inhibitor. The terminal part of the linker comprises the fluorophore NBD (7-nitro-1,2,3-benzoxadiazole). For this 8^th ECMC presentation, the results of the multi-step syntheses of these fluorescence probes will be presented as well as the cell bio-imaging works.