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

Reeder M. Robinson, Leticia Reyes, Ravyn M. Duncan, Haiyan Bian, Allen B. Reitz, Yefim Manevich, Jesse J. McClure, Matthew M. Champion, C. James Chou, Meahgen E. Sharik, Marta Chesi, Peter Leif Bergsagel, Nathan G. Dolloff

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalLeukemia
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Protein Disulfide-Isomerases
Multiple Myeloma
Proteasome Inhibitors
Click Chemistry
Small Molecule Libraries
Therapeutics
Peptide Mapping
Protein Folding
Standard of Care
Protein Isoforms
Proteins
Oxidative Stress
Homeostasis
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Robinson, R. M., Reyes, L., Duncan, R. M., Bian, H., Reitz, A. B., Manevich, Y., ... Dolloff, N. G. (Accepted/In press). Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma. Leukemia. https://doi.org/10.1038/s41375-018-0263-1

Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma. / Robinson, Reeder M.; Reyes, Leticia; Duncan, Ravyn M.; Bian, Haiyan; Reitz, Allen B.; Manevich, Yefim; McClure, Jesse J.; Champion, Matthew M.; Chou, C. James; Sharik, Meahgen E.; Chesi, Marta; Bergsagel, Peter Leif; Dolloff, Nathan G.

In: Leukemia, 01.01.2018.

Research output: Contribution to journalArticle

Robinson, RM, Reyes, L, Duncan, RM, Bian, H, Reitz, AB, Manevich, Y, McClure, JJ, Champion, MM, Chou, CJ, Sharik, ME, Chesi, M, Bergsagel, PL & Dolloff, NG 2018, 'Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma', Leukemia. https://doi.org/10.1038/s41375-018-0263-1
Robinson, Reeder M. ; Reyes, Leticia ; Duncan, Ravyn M. ; Bian, Haiyan ; Reitz, Allen B. ; Manevich, Yefim ; McClure, Jesse J. ; Champion, Matthew M. ; Chou, C. James ; Sharik, Meahgen E. ; Chesi, Marta ; Bergsagel, Peter Leif ; Dolloff, Nathan G. / Inhibitors of the protein disulfide isomerase family for the treatment of multiple myeloma. In: Leukemia. 2018.
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