4.7 Article

Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma

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LEUKEMIA
卷 33, 期 4, 页码 1011-1022

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-018-0263-1

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资金

  1. NIH/NCI [1R41CA213488-01]
  2. South Carolina Clinical & Translational Research Institute
  3. academic home at the Medical University of South Carolina (MUSC) [UL1 RR029882, UL1 TR000062]
  4. MUSC Hollings Cancer Center [P30 CA138313]
  5. Hollings Cancer Center T32 Ruth L. Kirschstein National Research Service Award Training Program T32 [CA193201]
  6. South Carolina Center of Biomedical Research Excellence (COBRE) in Oxidants, Redox Balance and Stress Signaling [P20GM103542]
  7. American Cancer Society [RSG-14-156-01-CDD]

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Multiple Myeloma (MM) is highly sensitive to disruptions in cellular protein homeostasis. Proteasome inhibitors (PIs) are initially effective in the treatment of MM, although cures are not achievable and the emergence of resistance limits the durability of responses. New therapies are needed for refractory patients, and those that combat resistance to standard of care agents would be particularly valuable. Screening of multiple chemical libraries for PI re-sensitizing compounds identified E61 as a potent enhancer of multiple PIs and MM specific activity. Using a tandem approach of click chemistry and peptide mass fingerprinting, we identified multiple protein disulfide isomerase (PDI) family members as the primary molecular targets of E61. PDIs mediate oxidative protein folding, and E61 treatment induced robust ER and oxidative stress responses as well as the accumulation of ubiquitinylated proteins. A chemical optimization program led to a new structural class of indene (exemplified by lead E64FC26), which are highly potent pan-style inhibitors of PDIs. In mice with MM, E64FC26 improved survival and enhanced the activity of bortezomib without any adverse effects. This work demonstrates the potential of E64FC26 as an early drug candidate and the strategy of targeting multiple PDI isoforms for the treatment of refractory MM and beyond.

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