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Clarifying the translational potential of B-I09

Nature Chemical Biology volume 16, page 1152 (2020)Cite this article

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To the Editor – Inositol-requiring enzyme 1 (IRE1) is a central regulator of the unfolded protein response (UPR), and inhibiting its activity is likely to be of benefit for treating diseases related to proteostasis. Hetz et al. recently published a Review Article in Nature Chemical Biology exploring pharmacological targeting of the UPR for disease intervention1 in which they discussed the efficacy of the IRE1 inhibitor B-I09 to induce leukemic regression without causing systemic toxicity in mouse models. They also pointed out a caveat that high concentrations of B-I09 were administered frequently using 100% DMSO as a carrier and suggested that this reduces the translational potential of B-I09. Representing the team leading to the development and optimization of B-109 for clinical use, we believe that some of the features of the compound and the characterization of its translational potential require clarification.

B-I09 was developed as a prodrug to target the RNase activity of IRE1, leading to the suppressed expression of XBP1s2. We have used chemical synthesis to tune prodrug stability within a series of B-I09 analogs and achieve spatiotemporal control of inhibitory activity3. Studies using B-I09 have been instrumental in validating the IRE1–XBP1 pathway as a therapeutic target in diseases. For instance, pharmacological inhibition of XBP1s using B-I09 phenocopies genetic deletion of XBP1s in mouse models of chronic lymphocytic leukemia, Burkitt’s lymphoma and chronic graft-versus-host disease (cGVHD)2,4,5. As demonstrated in ERAI reporter mice, B-I09 effectively blocks the RNase activity of IRE1 in dendritic cells6. To the best of our knowledge, B-I09 is the only IRE1–XBP1 inhibitor for which published pharmacokinetic data have guided dosing in mice2. The translational potential of B-I09 is highlighted by consistent results in suppression of XBP1s in targeted cells and amelioration of diseased conditions in various preclinical mouse models2,4,5,7,8. Notably, B-I09 appears to impose no systemic toxicity in treated mice, as documented in several preclinical studies2,4,5,7,8.

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References

  1. Hetz, C., Axten, J. M. & Patterson, J. B. Nat. Chem. Biol. 15, 764–775 (2019).

    Article  CAS  Google Scholar 

  2. Tang, C. H. et al. J. Clin. Invest. 124, 2585–2598 (2014).

    Article  CAS  Google Scholar 

  3. Shao, A. et al. J. Med. Chem. 62, 5404–5413 (2019).

    Article  CAS  Google Scholar 

  4. Xie, H. et al. J. Clin. Invest. 128, 1300–1316 (2018).

    Article  Google Scholar 

  5. Schutt, S. D. et al. Blood Adv. 2, 414–427 (2018).

    Article  CAS  Google Scholar 

  6. Tavernier, S. J. et al. Nat. Cell Biol. 19, 698–710 (2017).

    Article  CAS  Google Scholar 

  7. Tang, C. H. A. et al. Cancer Immunol. Res. 6, 696–710 (2018).

    Article  CAS  Google Scholar 

  8. Betts, B. C. et al. Front. Immunol. 9, 2887 (2018).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    Juan R. Del Valle

  2. Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, MN, USA

    Brian C. Betts

  3. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    Xue-Zhong Yu

  4. VIB-UGent Center for Inflammation Research, Ghent, Belgium

    Sophie Janssens & Bart N. Lambrecht

  5. Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    M. Celeste Simon

  6. The Wistar Institute, Philadelphia, PA, USA

    Chih-Chi Andrew Hu

Authors
  1. Juan R. Del Valle
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Corresponding author

Correspondence to Chih-Chi Andrew Hu.

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Competing interests

J.R.D. and C.-C.A.H. are named inventors of B-I09 and its analogs (Patent # US10,323,013). All other authors declare no competing interests.

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Del Valle, J.R., Betts, B.C., Yu, XZ. et al. Clarifying the translational potential of B-I09. Nat Chem Biol 16, 1152 (2020). https://doi.org/10.1038/s41589-020-00654-w

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