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Leukemia. 2017 Sep;31(9):1951-1961. doi: 10.1038/leu.2016.393. Epub 2017 Feb 2.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

Author information

1
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2
Arvinas LLC, New Haven, CT, USA.
3
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
4
Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA, USA.
5
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
6
Department of Chemistry, Yale University, New Haven, CT, USA.
7
Department of Pharmacology, Yale University, New Haven, CT, USA.

Abstract

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

PMID:
28042144
PMCID:
PMC5537055
DOI:
10.1038/leu.2016.393
[Indexed for MEDLINE]
Free PMC Article

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