Planta Med 2010; 76 - SL_38
DOI: 10.1055/s-0030-1264276

The pharmacophore of thapsigargin

S Christensen 1, D Skytte 1, H Liu 1, H Nielsen 1, L Svenningsen 1, C Jensen 1, J Møller 2
  • 1University of Copenhagen, Faculty of Pharmaceutical Sciences, Department of Medicinal Chemistry, Universitetsparken 2, 2100 Copehagen Ø, Denmark
  • 2University of Aarhus, Department of Physilogy and Biophysics, Ole Worms Alle blg 1185, DK-8000 Aarhus, Denmark

A derivative of thapsigargin (1) is currently in clinical phase 1 trials for treatment of prostate, bladder, and breast cancer. Thapsigargin has been targeted towards solid tumours by coupling the natural product to a peptide, which selectively is cleaved by enzymes present in excess in the cell walls of the blood vessels nourishing solid tumours. Human kallikrein 2 is an example of such a proteolytic enzyme [1]. The cytoxicity of thapsigargin relates to the ability to inhibit the sarco- or endoplasmic Ca2+ ATPase (SERCA). A pharmacophore model suggest that lipophilic interactions between the acyl groups at O-3, O-8, O-10 and CH3–15 are of major importance for the affinity to the binding cavity. Analysis of the X-ray structure of the complex of thapsigargin and SERCA [2] reveals that the segment F(834)FRY(837) andthe segment A(306)IPEGL(311) form the sides of the cavity.

Fig.1

Even though the angeloyl and acetyl groups are in very short distances from the transmembrane segments replacement of these groups with voluminous but flexible acyl groups only to a minor extent diminish the affinities of the analogues for SERCA. In contrast replacement of these acyl groups with voluminous and stiff groups like 4-benzylbenzoate severely reduces the binding affinity of the analogues.

Acknowledgements: This work is supported by the Danish Research Council for Strategic Research and the Danish Cancer Society.

References: 1. Christensen, SB. et al. (2009) Anti-cancer Agents Med Chem 9:276–294.

2. Toyoshima, C, Nomura, H. (2002) Nature 418: 605–611.