Fig. 3

Strategy to overcome thapsigargin’s toxicity. a Mipsagargin is a thapsigargin derivative coupled with a masking peptide that is a substrate for the carboxypeptidase prostate-specific membrane antigen (PSMA). This peptide reduces the affinity of these molecules toward SERCA in non-neoplastic cells. However, if mipsagargin intercepts PSMA on tumor cells or neoplastic neoangiogenic vessels are cleaved into a cytotoxic analog of thapsigargin (12-ADT-Asp) and diffuse into the cancer cells. b JQ-FT is a derivative of thapsigargin, 8-O-debutanoyl-thapsigargin, linked with folic acid. In tumor cells expressing folate (FA) receptor, JQ-FT enters through endocytosis and proteases release 8-O-debutanoyl-thapsigargin from FA directly into the cytosol of targeted cells. c Identification of SERCA inhibitors by high-throughput screening, ATPase activity assays (Ca²⁺-ATPase vs. Na⁺/K⁺-ATPase vs. H⁺/K⁺-ATPase) or in silico prediction