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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Vydáno v:	Blood Ročník 133; číslo 9; s. 952
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 28.02.2019
Témata:	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
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Abstract	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.
AbstractList	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.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. 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.
Author	Fischer, Eric S Gray, Nathanael S Dobrovolsky, Dennis Treon, Steven P Nowak, Radosław P Weinstock, David M Faust, Tyler Yang, Guang Li, Zhengnian Morrow, Sara Leahy, Catharine Donovan, Katherine A Wang, Eric S
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30545835$$D View this record in MEDLINE/PubMed
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SubjectTerms	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
Title	Bruton tyrosine kinase degradation as a therapeutic strategy for cancer
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