title: Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment.
abstract: Protein disulfide isomerase (PDI), an endoplasmic reticulum 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 need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a 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 MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity 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 toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDI-implicated pathways.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shili
authors.initials: S
authors.lastname: Xu
authors.forename: Alexey N
authors.initials: AN
authors.lastname: Butkevich
authors.forename: Roppei
authors.initials: R
authors.lastname: Yamada
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.forename: Roger
authors.initials: R
authors.lastname: Duncan
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Zandi
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D003545:Cysteine / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006652:Histological Techniques; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011422:Propionates / Q000737:chemistry; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D004151:Dipeptides; D011422:Propionates; D013876:Thiophenes; D019704:Protein Disulfide-Isomerases; D003545:Cysteine; C011537:propiolic acid