Design, synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties
Open accessAbstract
A new series of Proteolysis Targeting Chimeras (PROTACs) targeting Bruton's Tyrosine Kinase (BTK) was synthesized, with the goal of improving the pharmacokinetic properties of our previously reported PROTAC, MT802. We recently described the ability of MT802 to induce degradation of both wild-type and C481S mutant BTK in immortalized cells and patient-derived B-lymphocytes. However, the pharmacokinetic properties of MT802 were not suitable for further in vivo development. Therefore, we undertook a systematic medicinal chemistry campaign to overcome this issue and made a series of PROTACs with structural modifications to the linker and E3-recruiting ligand; more specifically, the new PROTACs were synthesized with different von Hippel-Lindau (VHL) and cereblon (CRBN) ligands while keeping the BTK ligand and linker length constant. This approach resulted in an equally potent PROTAC, SJF620, with a significantly better pharmacokinetic profile than MT802. This compound may hold promise for further in vivo exploration of BTK degradation.
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Several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and in vivo potencies were reported.
“Subsequently, several potent BTK PROTACs aimed at targeting mutant BTK in ibrutinib-resistant B cell malignancies with improved cellular activities and possessing in vivo potencies were reported by different groups [7, 44, 118–120].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [119]
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References 26 · Cited by 88
- Authors
- Jaime-Figueroa, S., Buhimschi, A. D., Toure, M., Hines, J., & Crews, C. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 3
- Pages
- 126877
- ISSN
- 0960-894X (ISSN-L)
- PMC
- PMC7318425
- OpenAlex
- W2994919776
- Cited by
- 88
- References
- 26
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 23 · 2021: 15 · 2020: 13
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R50CA211252, R35CA197589)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- PROTACs, Bruton's tyrosine kinase, pharmacokinetic properties, linker modification, B-cell lymphocytes, linker length
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Acetamides, Adenine, B-Lymphocytes, Binding Sites, Cell Line, Half-Life, Humans, Ligands, Piperidines, Drug Design, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Von Hippel-Lindau Tumor Suppressor Protein, Proteolysis, Molecular Docking Simulation
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