Proteolysis-Targeting Chimeras (PROTACs) targeting the BCR-ABL for the treatment of chronic myeloid leukemia – a patent review

ABSTRACT

Introduction

PROteolysis-TArgeting Chimeras (PROTACs) allow the selective degradation of a protein of interest (POI) by the ubiquitin-proteasome system (UPS). With this unique mechanism of action, the research and development of PROTACs that target the Breakpoint Cluster Region Abelson (BCR-ABL) tyrosine kinase (TK) has been increasing dramatically, as they are promising molecules in the treatment of Chronic Myeloid Leukemia (CML), one of the main hematological malignancies, which results from an uncontrolled myeloproliferation due to the constitutive activation of BCR-ABL.

Areas Covered

This review summarizes the patents/applications published in the online databases like Espacenet or World Intellectual Property Organization regarding PROTACs that promote BCR-ABL degradation. Patents will be described mostly in terms of chemical structure, biochemical/pharmacological activities, and potential clinical applications.

Expert opinion

The recent discovery of the enormous potential of PROTACs led to the creation of new compounds capable of degrading BCR-ABL for the treatment of CML. Although still in reduced numbers, and in the pre-clinical phase of development, some compounds have already been shown to overcome some of the difficulties presented by conventional BCR-ABL inhibitors, such as the well-known imatinib. Therefore, it is very likely that some of the present PROTACs will enter future CML therapy in the coming years.

KEYWORDS:

• Bifunctional molecules
• Breakpoint Cluster Region Abelson (BCR-ABL)
• Cancer
• Chronic Myeloid Leukemia (CML)
• Degraders
• Proteolysis targeting chimeras (PROTACs)
• Tyrosine kinase (TK)
• Targeted protein degradation (TPD)

Article highlights

• The oncogenic fusion Breakpoint Cluster Region Abelson (BCR-ABL) tyrosine kinase (TK) protein is involved in the development of Chronic Myeloid Leukemia (CML) and is considered the main therapeutic target of this type of hematological cancer.

• The main form of treatment for CML currently consists of the oral administration of tyrosine kinase inhibitors (TKIs). However, the emergence of resistance and overexpression of the target protein hamper their use.

• PROteolysis-TArgeting Chimeras (PROTACs) targeting the BCR-ABL protein are innovative heterobifunctional compounds that allow the selective degradation of BCR-ABL through the ubiquitin-proteasome system (UPS), including the degradation of mutant forms of BCR-ABL.

• In 2017, Yale University published the first patent filing claiming PROTACs targeting BCR-ABL, with very promising results.

• Over the last few years, the number of patents/patent applications of PROTACs targeting the BCR-ABL has been growing, proving their promising potential for the treatment of CML.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

Conceptualization, A.T.S Vicente and J.A.R Salvador; writing – original draft preparation, A.T.S Vicente.; writing – review and editing, A.T.S Vicente and J.A.R Salvador; supervision, J.A.R Salvador; All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This paper was funded by the Strategic Plan - Center for Innovative Biomedicine and Biotechnology funds via Portuguese Foundation for Science and Technology (FCT) under Project UIDB/04539/2020.