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Tuning isoform selectivity and bortezomib sensitivity with a new class of alkenyl indene PDI inhibitor
Reeder M Robinson1, Leticia Reyes1, Ravyn M Duncan1
1Department of Cell and Molecular Pharmacology & Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC, USA.
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.
Insights
New indene compounds targeting protein disulfide isomerase (PDI) show promise for treating multiple myeloma. These PDI inhibitors enhance proteasome inhibitor efficacy, inducing cancer cell death and overcoming drug resistance.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Protein disulfide isomerase (PDI) is a key target in cancer therapy.
- PDI inhibitors show potential in inducing apoptosis and overcoming drug resistance, but clinical development is pending.
- Previous research identified E64FC26 as a potent pan-PDI inhibitor enhancing proteasome inhibitor effects in multiple myeloma (MM).
Purpose of the Study:
- To synthesize and characterize a novel library of indene-based PDI inhibitors.
- To establish structure-activity relationships (SAR) for indene compounds in potentiating proteasome inhibitors.
- To validate PDI as a therapeutic target in MM, both as a single agent and in combination therapy.
Main Methods:
- Novel nucleophilic aromatic ring cyclization and dehydration reactions were used to synthesize indene derivatives from precursor ketones.
- Structure-activity relationships (SAR) were determined by evaluating PDI inhibition and bortezomib (Btz) potentiation in MM cells.
- The effects of PDI inhibition on endoplasmic reticulum (ER) stress and oxidative stress were assessed by monitoring protein accumulation and UPR biomarkers (ATF4, CHOP, Nrf2).
Main Results:
- A diverse library of indene-containing molecules was generated with varying PDI inhibitory and proteasome inhibitor potentiating activities.
- A strong correlation was observed between PDI inhibition potency and bortezomib potentiation in MM cells.
- PDI inhibition induced ER and oxidative stress, characterized by misfolded protein accumulation and upregulation of ATF4, CHOP, and Nrf2.
Conclusions:
- This study characterizes a new chemical class of indene-based PDI inhibitors.
- Detailed SAR provides insights into the pharmacophore for PDI inhibition and proteasome inhibitor potentiation.
- The findings further support PDI as a viable therapeutic target for MM treatment, alone or in combination with proteasome inhibitors.
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