Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors
Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors
Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.
131-152
Packham, Graham
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Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Arthur, Rachael
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29 June 2020
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Steele, Andrew
4349f6aa-2e3a-49a8-be73-7716056ae089
Arthur, Rachael
5b9a8d13-1f70-40a3-8e30-741a8ad19068
Packham, Graham, Valle-Argos, Beatriz, Steele, Andrew and Arthur, Rachael
(2020)
Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors.
Open Exploration Publishing, 1, .
(doi:10.37349/etat.2020.00009).
Abstract
Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.
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Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors
- Accepted Manuscript
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Development of PROTAC
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Accepted/In Press date: 24 April 2020
Published date: 29 June 2020
Identifiers
Local EPrints ID: 444121
URI: http://eprints.soton.ac.uk/id/eprint/444121
PURE UUID: f6df2560-3262-44bb-a611-6f5f58384607
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Date deposited: 28 Sep 2020 16:30
Last modified: 17 Mar 2024 03:24
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Author:
Beatriz Valle-Argos
Author:
Rachael Arthur
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