ArticleEuropean journal of medicinal chemistry2020
Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor.
Article in European journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 24 citations in OpenAlex.
- FTO-mediated m6A modification of protein disulfide-isomerase activates VEGFA-VEGFR2 to suppress programmed cell death in osteosarcoma.The Journal of pathology · 2026Article
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- The beneficial effect of hepatic ER stress-associated protein PDI on obesity-associated glucose dysregulation.Nutrition & metabolism · 2025Article
- Downregulation of PDIA4 inhibits proliferation and migration in human oral squamous cell carcinoma.Hereditas · 2025Article
- Article
- Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma.Biomolecules · 2025Article
- Leveraging a disulfidptosis-based signature to characterize heterogeneity and optimize treatment in multiple myeloma.Frontiers in immunology · 2025Article
- Pan-Inhibition of Protein Disulfide Isomerase Caused Cell Death through Disrupting Cellular Proteostasis in Pancreatic Ductal Adenocarcinoma Cells.International journal of molecular sciences · 2023Article
- Prolyl 4-hydroxylase subunit beta (P4HB) could serve as a prognostic and radiosensitivity biomarker for prostate cancer patients.European journal of medical research · 2023Article
- Deep Vein Thrombosis Is Facilitated by Endothelial-Derived Extracellular Vesicles via the PDI-GRP94-GPIIb/IIIa Pathway in Mice.Journal of clinical medicine · 2023Article
- Protein Disulfide Isomerases Function as the Missing Link Between Diabetes and Cancer.Antioxidants & redox signaling · 2022Review
- PDI inhibitor LTI6426 enhances panobinostat efficacy in preclinical models of multiple myeloma.Cancer chemotherapy and pharmacology · 2022Article
- PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis.Frontiers in oncology · 2022Article
- Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study.Frontiers in oncology · 2022Article
- Article
- Review
- ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors.Cancer research · 2020Article
- The Role of ERO1α in Modulating Cancer Progression and Immune Escape.Journal of cancer immunology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.