Cargando…
Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase
Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been de...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131351/ https://www.ncbi.nlm.nih.gov/pubmed/30202081 http://dx.doi.org/10.1038/s41598-018-31913-5 |
_version_ | 1783354086518685696 |
---|---|
author | Shibata, Norihito Shimokawa, Kenichiro Nagai, Katsunori Ohoka, Nobumichi Hattori, Takayuki Miyamoto, Naoki Ujikawa, Osamu Sameshima, Tomoya Nara, Hiroshi Cho, Nobuo Naito, Mikihiko |
author_facet | Shibata, Norihito Shimokawa, Kenichiro Nagai, Katsunori Ohoka, Nobumichi Hattori, Takayuki Miyamoto, Naoki Ujikawa, Osamu Sameshima, Tomoya Nara, Hiroshi Cho, Nobuo Naito, Mikihiko |
author_sort | Shibata, Norihito |
collection | PubMed |
description | Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding of the impact of BCR-ABL degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent BCR-ABL degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the BCR-ABL protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48 h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of BCR-ABL levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that BCR-ABL degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor. |
format | Online Article Text |
id | pubmed-6131351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61313512018-09-13 Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase Shibata, Norihito Shimokawa, Kenichiro Nagai, Katsunori Ohoka, Nobumichi Hattori, Takayuki Miyamoto, Naoki Ujikawa, Osamu Sameshima, Tomoya Nara, Hiroshi Cho, Nobuo Naito, Mikihiko Sci Rep Article Chronic myelogenous leukemia (CML) is characterized by the oncogenic fusion protein, BCR-ABL protein kinase, against which clinically useful inhibitors have been developed. An alternative approach to treat CML is to degrade the BCR-ABL protein. Recently, potent degraders against BCR-ABL have been developed by conjugating dasatinib to ligands for E3 ubiquitin ligases. Since the degraders contain the dasatinib moiety, they also inhibit BCR-ABL kinase activity, which complicates our understanding of the impact of BCR-ABL degradation by degraders in CML growth inhibition. To address this issue, we chose DAS-IAP, as a potent BCR-ABL degrader, and developed a structurally related inactive degrader, DAS-meIAP, which inhibits kinase activity but does not degrade the BCR-ABL protein. DAS-IAP showed slightly weaker activity than DAS-meIAP in inhibiting cell growth when CML cells were treated for 48 h. However, DAS-IAP showed sustained growth inhibition even when the drug was removed after short-term treatment, whereas CML cell growth rapidly resumed following removal of DAS-meIAP and dasatinib. Consistently, suppression of BCR-ABL levels and downstream kinase signaling were maintained after DAS-IAP removal, whereas kinase signaling rapidly recovered following removal of DAS-meIAP and dasatinib. These results indicate that BCR-ABL degrader shows more sustained inhibition of CML cell growth than ABL kinase inhibitor. Nature Publishing Group UK 2018-09-10 /pmc/articles/PMC6131351/ /pubmed/30202081 http://dx.doi.org/10.1038/s41598-018-31913-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Shibata, Norihito Shimokawa, Kenichiro Nagai, Katsunori Ohoka, Nobumichi Hattori, Takayuki Miyamoto, Naoki Ujikawa, Osamu Sameshima, Tomoya Nara, Hiroshi Cho, Nobuo Naito, Mikihiko Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title | Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title_full | Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title_fullStr | Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title_full_unstemmed | Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title_short | Pharmacological difference between degrader and inhibitor against oncogenic BCR-ABL kinase |
title_sort | pharmacological difference between degrader and inhibitor against oncogenic bcr-abl kinase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131351/ https://www.ncbi.nlm.nih.gov/pubmed/30202081 http://dx.doi.org/10.1038/s41598-018-31913-5 |
work_keys_str_mv | AT shibatanorihito pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT shimokawakenichiro pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT nagaikatsunori pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT ohokanobumichi pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT hattoritakayuki pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT miyamotonaoki pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT ujikawaosamu pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT sameshimatomoya pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT narahiroshi pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT chonobuo pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase AT naitomikihiko pharmacologicaldifferencebetweendegraderandinhibitoragainstoncogenicbcrablkinase |