Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

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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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Most cited references 79

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Induced protein degradation: an emerging drug discovery paradigm

Ashton C Lai, Craig M Crews (2016)

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.

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Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

Jennifer A. Woyach, Richard R Furman, Ta-Ming Liu … (2014)

Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).

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Catalytic in vivo protein knockdown by small-molecule PROTACs.

Daniel Bondeson, Alina Mares, Ian E D Smith … (2015)

The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation. These compounds behave catalytically in their ability to induce the ubiquitination of super-stoichiometric quantities of proteins, providing efficacy that is not limited by equilibrium occupancy. We present two PROTACs that are capable of specifically reducing protein levels by >90% at nanomolar concentrations. In addition, mouse studies indicate that they provide broad tissue distribution and knockdown of the targeted protein in tumor xenografts. Together, these data demonstrate a protein knockdown system combining many of the favorable properties of small-molecule agents with the potent protein knockdown of RNAi and CRISPR.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101770662

Journal ID (nlm-ta): Explor Target Antitumor Ther

Journal ID (iso-abbrev): Explor Target Antitumor Ther

Title: Exploration of targeted anti-tumor therapy

ISSN (Electronic): 2692-3114

Publication date Nihms-submitted: 03 September 2020

Publication date (Electronic): 29 June 2020

Publication date PMC-release: 10 September 2020

Volume: 1

Pages: 131-152

Affiliations

[1 ]Cancer Research UK Centre, Cancer Sciences, Faculty of Medicine, University of Southampton, SO16 6YD Southampton, UK

[2 ]Institute for Life Sciences, University of Southampton, University Road, Highfield Campus, SO17 1BJ, Southampton, UK

Author notes

[* ] Correspondence: Graham Packham, Cancer Sciences, Somers Research Building (MP824), Southampton General Hospital, SO16 6YD Southampton, UK. gpackham@ 123456soton.ac.uk

Academic Editor: Matthias Baud, University of Southampton, UK

Author information

Rachael Arthur https://orcid.org/0000-0002-3294-372X

Beatriz Valle-Argos http://orcid.org/0000-0003-3334-3387

Andrew J. Steele http://orcid.org/0000-0003-0667-1596

Graham Packham http://orcid.org/0000-0002-9232-5691

Article

Manuscript ID: EMS94608

DOI: 10.37349/etat.2020.00009

PMC ID: 7116064

SO-VID: 004b5d7f-519d-4b03-958a-9d815559b7a1

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This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, 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.

Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors

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Neuronal Signaling

Most cited references 79

Induced protein degradation: an emerging drug discovery paradigm

Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

Catalytic in vivo protein knockdown by small-molecule PROTACs.

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