Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range.

Camille Le Guilcher,Tomas Luyten,Mathieu Pucheault,Olivier Dellis,Jan B Parys

doi:10.3390/ijms21249777

Abstract

The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a Ki ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP3 receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.

Highlights

The control of Ca2+ homeostasis is a challenging process for the cell
During the last 15 years, the two main proteins responsible for store-operated calcium entry (SOCE) have been unveiled: STIM1, the Ca2+-sensor protein localized in the endoplasmic reticulum (ER) membrane, and Orai1, the pore-forming protein localized in the plasma membrane
Using a previously described methodology, these compounds were prepared in a one-pot procedure using air-stable amine borane complexes and Grignard reagents formed under Barbier conditions

Summary

Introduction

Many cellular functions, including contraction, differentiation, and proliferation, are regulated by an increase of the intracellular Ca2+ ion concentration [1] These increases are commonly due to the release of Ca2+ ions from internal stores (mainly the endoplasmic reticulum (ER)) and to an influx of Ca2+ ions from the extracellular space. In lymphocytes in particular, cell stimulation induces the synthesis of inositol 1,4,5-trisphosphate (IP3) allowing the release of Ca2+ ions out of the ER through the IP3 receptor (IP3R). This depletion activates a Ca2+ influx known as store-operated calcium entry (SOCE) [2]. Even if Orai channels are present and the leukocyte repertoire unchanged, the immune system remains deficient

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Conclusion