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

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 c

SUBMITTER: Robinson RM 

PROVIDER: S-EPMC7212515 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature