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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
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
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
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, 131-152. (doi:10.37349/etat.2020.00009).

Record type: Article

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 - Version of Record
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More information

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
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596

Catalogue record

Date deposited: 28 Sep 2020 16:30
Last modified: 18 Feb 2021 17:17

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Contributors

Author: Graham Packham ORCID iD
Author: Beatriz Valle-Argos
Author: Andrew Steele ORCID iD
Author: Rachael Arthur

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