Syrbactin-class dual constitutive- and immuno-proteasome inhibitor TIR-199 impedes myeloma-mediated bone degeneration in vivo

Vasudha Tandon, Ruturajsinh M. Vala, Albert Chen, Robert L. Sah, Hitendra M. Patel, Michael C. Pirrung, Sourav Banerjee (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
43 Downloads (Pure)

Abstract

Proteasome-addicted neoplastic malignancies present a considerable refractory and relapsed phenotype with patients exhibiting drug resistance and high mortality rates. To counter this global problem, novel proteasome-based therapies are being developed. In the current study, we extensively characterize TIR-199, a syrbactin-class proteasome inhibitor derived from a plant virulence factor of bacterium Pseudomonas syringae pv syringae. We report that TIR-199 is a potent constitutive and immunoproteasome inhibitor, capable of inducing cell death in multiple myeloma, triple-negative breast cancer, (TNBC) and non-small cell lung cancer lines. TIR-199 also effectively inhibits the proteasome in primary myeloma cells of patients, and bypasses the PSMB5 A49T+A50V bortezomib-resistant mutant. TIR-199 treatment leads to accumulation of canonical proteasome substrates in cells, it is specific, and does not inhibit 50 other enzymes tested in vitro. The drug exhibits synergistic cytotoxicity in combination with proteasome-activating kinase DYRK2 inhibitor LDN192960. Furthermore, low-doses of TIR-199 exhibits in vivo activity by delaying myeloma-mediated bone degeneration in a mouse xenograft model. Together, our data indicates that proteasome inhibitor TIR-199 could indeed be a promising next-generation drug within the repertoire of proteasome-based therapeutics.

Original languageEnglish
Article numberBSR20212721
Pages (from-to)1-13
Number of pages13
JournalBioscience Reports
Volume42
Issue number2
Early online date28 Jan 2022
DOIs
Publication statusPublished - 11 Feb 2022

Keywords

  • cancer
  • Proteasome inhibitor
  • breast cancers
  • multiple myeloma
  • drug resistance
  • enzyme activity
  • proteasome inhibitor

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