Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells

Schild, Achille; Bhardwaj, Rajesh; Wenger, Nicolas; Tscherrig, Dominic; Kandasamy, Palanivel; Dernič, Jan; Baur, Roland; Peinelt, Christine; Hediger, Matthias A.; Lochner, Martin (2020). Synthesis and Pharmacological Characterization of 2-Aminoethyl Diphenylborinate (2-APB) Derivatives for Inhibition of Store-Operated Calcium Entry (SOCE) in MDA-MB-231 Breast Cancer Cells. International journal of molecular sciences, 21(16) Molecular Diversity Preservation International MDPI 10.3390/ijms21165604

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Calcium ions regulate a wide array of physiological functions including cell differentiation, proliferation, muscle contraction, neurotransmission, and fertilization. The endoplasmic reticulum (ER) is the major intracellular Ca2+ store and cellular events that induce ER store depletion (e.g., activation of inositol 1,4,5-triphosphate (IP3) receptors) trigger a refilling process known as store-operated calcium entry (SOCE). It requires the intricate interaction between the Ca2+ sensing stromal interaction molecules (STIM) located in the ER membrane and the channel forming Orai proteins in the plasma membrane (PM). The resulting active STIM/Orai complexes form highly selective Ca2+ channels that facilitate a measurable Ca2+ influx into the cytosol followed by successive refilling of the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). STIM and Orai have attracted significant therapeutic interest, as enhanced SOCE has been associated with several cancers, and mutations in STIM and Orai have been linked to immunodeficiency, autoimmune, and muscular diseases. 2-Aminoethyl diphenylborinate (2-APB) is a known modulator and depending on its concentration can inhibit or enhance SOCE. We have synthesized several novel derivatives of 2-APB, introducing halogen and other small substituents systematically on each position of one of the phenyl rings. Using a fluorometric imaging plate reader (FLIPR) Tetra-based calcium imaging assay we have studied how these structural changes of 2-APB affect the SOCE modulation activity at different compound concentrations in MDA-MB-231 breast cancer cells. We have discovered 2-APB derivatives that block SOCE at low concentrations, at which 2-APB usually enhances SOCE.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Schild, Achille Eros Ulisse; Bhardwaj, Rajesh; Wenger, Nicolas; Tscherrig, Dominic Armin; Kandasamy, Palanivel; Dernič, Jan; Baur, Roland; Peinelt, Christine; Hediger, Matthias and Lochner, Martin

Subjects:

600 Technology > 610 Medicine & health
500 Science > 540 Chemistry
500 Science > 570 Life sciences; biology

ISSN:

1661-6596

Publisher:

Molecular Diversity Preservation International MDPI

Funders:

[4] Swiss National Science Foundation

Language:

English

Submitter:

Martin Lochner

Date Deposited:

13 Aug 2020 17:06

Last Modified:

11 Dec 2020 09:46

Publisher DOI:

10.3390/ijms21165604

PubMed ID:

32764353

BORIS DOI:

10.7892/boris.145882

URI:

https://boris.unibe.ch/id/eprint/145882

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