| Ovarian cancer is one of the leading cancers causing women's death in the United States mainly due to its late diagnosis and resistance to current clinically used drugs. Therefore, the development of novel potent drugs for the treatment of ovarian cancer is in urgent medical need.;Protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) chaperone protein, catalyzes disulfide bond breakage, formation and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a dearth of potent, selective and safe small-molecule inhibitors of PDI. In chapter III, I report a novel class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and mass spectrometry, we established that PACMA 31, one of the most active analogs, act as irreversible small-molecule inhibitors of PDI. We also demonstrated that PDI is essential for the survival and proliferation of human ovarian cancer cells. In vivo PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing damage in normal tissues. These irreversible small-molecule PDI inhibitors represent a new approach for the development of targeted anticancer agents for ovarian cancer therapy, and can also serve as useful probes for investigating the biology of PDI-implicated pathways.;On the other hand, despite abundant evidence that ovarian cancer progression is dependent upon IL-6/Stat3 signaling, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is unclear in ovarian cancer, and there is a dearth of small-molecule inhibitors of gp130. In chapter V, I report that gp130 is an attractive drug target in ovarian cancer due to its role in promoting ovarian cancer progression via the activation of its downstream Stat3 signaling, and identify a small-molecule gp130 inhibitor SC144 with anticancer activity. In vitro, SC144 exhibits potency in human ovarian cancer cells without cytotoxicity in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and thus inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand triggered signaling. In vivo, SC144 suppresses tumor growth with oral bioavailability in a mouse xenograft model of human ovarian cancer without causing damage to normal tissues.;My discovery of PDI and gp130 as potential drug targets for ovarian cancer treatment, and the identification of PACMA 31 and SC144 as inhibitors of PDI and gp130, respectively, not only promote the development of targeted therapy, but also bring new hope for cancer patients. |
