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

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...

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Bibliographic Details
Published in:Leukemia 2017-09, Vol.31 (9), p.1951-1961
Main Authors: Saenz, D T, Fiskus, W, Qian, Y, Manshouri, T, Rajapakshe, K, Raina, K, Coleman, K G, Crew, A P, Shen, A, Mill, C P, Sun, B, Qiu, P, Kadia, T M, Pemmaraju, N, DiNardo, C, Kim, M-S, Nowak, A J, Coarfa, C, Crews, C M, Verstovsek, S, Bhalla, K N
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Animals
Antigens, CD34
Apoptosis
Apoptosis - drug effects
Azepines - pharmacology
Azepines - therapeutic use
Bcl protein
Bcl-x protein
Bet protein
Biocompatibility
Biomedical materials
c-Myc protein
CD34 antigen
Cell Cycle Proteins
Cell Line, Tumor
Cells (biology)
Cyclin-dependent kinase 4
Cytometry
Degradation
Depletion
Hematopoietic stem cells
Humans
In vitro methods and tests
In vivo methods and tests
Inhibitors
Janus kinase 2
Leukemia
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - pathology
Mice
mRNA
Myc protein
Myeloproliferative Disorders - pathology
Nitriles
Nuclear Proteins - metabolism
Perturbation
Progenitor cells
Protein arrays
Proteins
Proteolysis
Pyrazoles - pharmacology
Pyrimidines
Ribonucleic acid
RNA
Stat3 protein
Surgical implants
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Thalidomide - therapeutic use
Transcription Factors - metabolism
Tumor Burden - drug effects
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2016.393