Bruton tyrosine kinase degradation as a therapeutic strategy for cancer

The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule-in...

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Published in:Blood Vol. 133; no. 9; p. 952
Main Authors: Dobrovolsky, Dennis, Wang, Eric S, Morrow, Sara, Leahy, Catharine, Faust, Tyler, Nowak, Radosław P, Donovan, Katherine A, Yang, Guang, Li, Zhengnian, Fischer, Eric S, Treon, Steven P, Weinstock, David M, Gray, Nathanael S
Format: Journal Article
Language:English
Published: United States 28.02.2019
Subjects:
Agammaglobulinaemia Tyrosine Kinase - metabolism
Animals
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Humans
Ikaros Transcription Factor - metabolism
Lymphoma, Mantle-Cell - drug therapy
Lymphoma, Mantle-Cell - enzymology
Lymphoma, Mantle-Cell - pathology
Mice
Mice, Inbred NOD
Mice, SCID
Proteolysis
Pyrazoles - pharmacology
Pyrimidines - pharmacology
Signal Transduction
Small Molecule Libraries - pharmacology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
ISSN:1528-0020, 1528-0020
Online Access:Get more information
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Summary:The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule-induced BTK degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in potent suppression of signaling and proliferation in cancer cells and that BTK degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading BTK, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, "triple degradation" may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2018-07-862953