caa a22 4500 445314028 CHVBK 20180627064139.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s11095-010-0249-9 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0249-9 Chemical Inhibitors of the Calcium Entry Channel TRPV6 [Elektronische Daten] [Christopher Landowski, Katrin Bolanz, Yoshiro Suzuki, Matthias Hediger] ABSTRACT: Purpose: Calcium entry channels in the plasma membrane are thought to play a major role in maintaining cellular Ca2+ levels, crucial for growth and survival of normal and cancer cells. The calcium-selective channel TRPV6 is expressed in prostate, breast, and other cancer cells. Its expression coincides with cancer progression, suggesting that it drives cancer cell growth. However, no specific inhibitors for TRPV6 have been identified thus far. Methods: To develop specific TRPV6 inhibitors, we synthesized molecules based on the lead compound TH-1177, reported to inhibit calcium entry channels in prostate cancer cells in vitro and in vivo. Results: We found that one of our compounds (#03) selectively inhibited TRPV6 over five times better than TRPV5, whereas TH-1177 and the other synthesized compounds preferentially inhibited TRPV5. The IC50 value for growth inhibition by blocking endogenous Ca2+ entry channels in the LNCaP human prostate cancer cell line was 0.44 ± 0.07μM compared to TH-1177 (50 ± 0.4μM). Conclusions: These results suggest that compound #03 is a relatively selective and potent inhibitor for TRPV6 and that it is an interesting lead compound for the treatment of prostate cancer and other cancers of epithelial origin. Springer Science+Business Media, LLC, 2010 breast cancer nationallicence calcium channel nationallicence chemical inhibitors nationallicence prostate cancer nationallicence TRPV6 nationallicence CRAC : Ca2+ release-activated Ca2+ nationallicence FBS : fetal bovine serum nationallicence LNCaP : lymph node carcinoma of the prostate nationallicence NFAT : nuclear factor of activated T-cells nationallicence NMM : N-methylmorpholine nationallicence Orai1 : calcium release-activated calcium channel protein 1 nationallicence PyBOP : Benzotriazol-1-yl-oxytripyrrolidinophosphonium nationallicence SCID : severe combined immunodeficiency nationallicence SOC : store-operated calcium channel nationallicence STIM1 : stromal interaction molecule 1 nationallicence THF : Tetrahydrofuran nationallicence TRP : transient receptor potential nationallicence Landowski Christopher VTT Technical Research Center of Finland, Espoo, Finland aut Bolanz Katrin Agroscope, Swiss Federal Office for Agriculture, Bern, Switzerland aut Suzuki Yoshiro Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland aut Hediger Matthias Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 322-330 0724-8741 28:2<322 2011 28 11095 https://doi.org/10.1007/s11095-010-0249-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0249-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Landowski Christopher VTT Technical Research Center of Finland, Espoo, Finland aut NATIONALLICENCE 700 1- Bolanz Katrin Agroscope, Swiss Federal Office for Agriculture, Bern, Switzerland aut NATIONALLICENCE 700 1- Suzuki Yoshiro Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland aut NATIONALLICENCE 700 1- Hediger Matthias Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012, Bern, Switzerland aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 322-330 0724-8741 28:2<322 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence SWISSBIB 445314028 BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer