Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 21, Issue 38, Pages 5501-5517Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1381612821666151002112824
Keywords
Thapsigargin; mipsagargin; drug development; clinical trials; structure activity relationships; prostate specific antigen; prostate specific membrane antigen; prodrug; anti-angiogenesis
Categories
Funding
- Danish Cancer Society
- GenSpera
- Danish Strategic Research Council
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Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.
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