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DOI: 10.1055/s-0030-1264276
The pharmacophore of thapsigargin
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.
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.