Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 186, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.111906
Keywords
Protein disulfide isomerase (PDI); Multiple myeloma; Proteasome inhibitor; Drug resistance; ER stress; UPR
Categories
Funding
- South Carolina Center of Biomedical Research Excellence (COBRE) in Oxidants, Redox Balance and Stress Signaling [P20GM103542]
- American Cancer Society [RSG-14-156-01-CDD]
- NIH/NCI [1R41CA213488, R42CA213488]
- South Carolina Clinical & Translational Research Institute
- Medical University of South Carolina (MUSC) [UL1 RR029882, UL1 TR000062]
- Hollings Cancer Center T32 Ruth L Kirschstein National Research Service Award Training Program T32 [CA193201]
- MUSC Hollings Cancer Center [P30 CA138313]
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Protein disulfide isomerase (PDI, PDIA1) is an emerging therapeutic target in oncology. PDI inhibitors have demonstrated a unique propensity to selectively induce apoptosis in cancer cells and overcome resistance to existing therapies, although drug candidates have not yet progressed to the stage of clinical development. We recently reported the discovery of lead indene compound E64FC26 as a potent pan-PDI inhibitor that enhances the cytotoxic effects of proteasome inhibitors in panels of Multiple Myeloma (MM) cells and MM mouse models. An extensive medicinal chemistry program has led to the generation of a diverse library of indene-containing molecules with varying degrees of proteasome inhibitor potentiating activity. These compounds were generated by a novel nucleophilic aromatic ring cyclization and dehydration reaction from the precursor ketones. The results provide detailed structure activity relationships (SAR) around this indene pharmacophore and show a high degree of correlation between potency of PDI inhibition and bortezomib (Btz) potentiation in MM cells. Inhibition of PDI leads to ER and oxidative stress characterized by the accumulation of misfolded poly-ubiquitinated proteins and the induction of UPR biomarkers ATF4, CHOP, and Nrf2. This work characterizes the synthesis and SAR of a new chemical class and further validates PDI as a therapeutic target in MM as a single agent and in combination with proteasome inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.
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