Abstract 3760: XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models

Abstract

Abstract Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers, including ovarian, prostate, and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 is a synthetic small molecule displaying an excellent docking with the human PDI. XCE853 inhibits in vitro recombinant PDI activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis. XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types. Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment. Altogether, these data support further efforts on this drug candidate to initiate the preclinical studies and to define the most relevant human tumor types. Citation Format: Gregoire P. Prevost, Marine Garrido, Maria Serova, Jean François Briand, Mathieu Gutmann, Patrick Ladam, Denis Carniato, Annemilai Tijeras-Raballand, Armand De Grammont, Anne Chauchereau, Marc-Henry Pitty, Paul Foster. XCE853 is a promising protein disulfide isomerase (PDI) inhibitor exhibiting a strong inhibitory activity in preclinical tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3760.