Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor

• Published in: European journal of medicinal chemistry Vol. 186; p. 111906
• Main Authors: Robinson, Reeder M., Reyes, Leticia, Duncan, Ravyn M., Bian, Haiyan, Strobel, Eric D., Hyman, Sarah L., Reitz, Allen B., Dolloff, Nathan G.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-01-2020
• Subjects: Bortezomib - chemical synthesis; Bortezomib - chemistry; Bortezomib - pharmacology; Cell Line; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug resistance; ER stress; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Molecular Structure; Multiple myeloma; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - metabolism; Proteasome inhibitor; Proteasome Inhibitors - chemical synthesis; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Protein disulfide isomerase (PDI); Protein Disulfide-Isomerases - antagonists & inhibitors; Protein Disulfide-Isomerases - metabolism; Structure-Activity Relationship; UPR; ER stress; Protein disulfide isomerase (PDI); Drug resistance; Proteasome inhibitor; UPR; Multiple myeloma
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111906

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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•Indene PDI inhibitors are a new class of therapeutic for the treatment of cancer.•Indene derivatives exhibit structure activity relationships in PDI activity assays.•Indene SAR in vitro correlates with bortezomib sensitization in myeloma cell models.•ER stress pathway biomarkers are key indicators of indene activity in myeloma cells.•PDI isoform selectivity is tunable with modification to the indene scaffold.