Delineating the role of cooperativity in the design of potent PROTACs for BTK
Open accessAbstract
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.
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Linker length plays an important role in PROTAC potency.
“The length of linker plays an important role in the potency of PROTAC molecules[29,30].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [30]
In a recent report of a BTK degrader, target degradation varied significantly between the spleen and lung despite similar distribution, potentially due to differences in the tissue-specific levels of CRBN.
“In a recent report of a BTK degrader, target degradation varied significantly between the spleen and lung despite similar distribution, potentially due to differences in the tissue-specific levels of CRBN.44”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [44]
Several studies reported successful conversion of either a reversible ibrutinib scaffold or a different noncovalent analog derived from a previously published covalent BTK inhibitor into BTK degraders.
“Subsequently, several studies reported successful conversion of either a reversible ibrutinib scaffold 42,43 or a different noncovalent analog derived from a previously published covalent BTK inhibitor 44,45 into BTK degraders.”
From Bruton tyrosine kinase degradation as a therapeutic strategy for cancer (2019) · cites this paper as [44]
BTK has been the subject of intense PROTAC molecule experimentation across academia and industry.
“and has been the subject of intense PROTAC molecule experimentation across academia and industry166–168”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [167]
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 [7]
Many PROTACs are not completely selective and can degrade proteins other than their desired targets.
“In addition, many PROTACs are not completely selective and can degrade proteins other than their desired targets [7, 90, 204, 205].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [7]
A CRBN-recruiting, IMiD-based PROTAC targeting the BTK tyrosine kinase also degrades the phthalimide-binding neo-substrates IKZF1 and IKZF3, leading to a synergistic and beneficial effect on mantle cell lymphoma.
“For example, a CRBN-recruiting, IMiD-based PROTAC targeting the BTK tyrosine kinase also degrades the phthalimide-binding neo-substrates IKFZ1 and IKFZ3, leading to a synergistic and beneficial effect on mantle cell lymphoma 40,54 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [54]
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PROTACs: A novel strategy for cancer therapy
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Harnessing the Power of Proteolysis for Targeted Protein Inactivation
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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
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- Authors
- Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., Feng, X., Chang, J. S., Uccello, D. P., Young, J. A., Garcia-Irrizary, C. N., Czabaniuk, L., Schuff, B., Oliver, R., Montgomery, J., Hayward, M. M., Coe, J., Chen, J., Niosi, M., Luthra, S., Shah, J. C., El-Kattan, A., Qiu, X., West, G. M., Noe, M. C., Shanmugasundaram, V., Gilbert, A. M., Brown, M. F., & Calabrese, M. F.
- Affiliations
- Pfizer (United States) (US)
- Medicine Design, Pfizer Worldwide Research and Development, Groton, CT 06340;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-07-16
- Volume
- 115
- Issue
- 31
- Pages
- E7285-E7292
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6077745
- OpenAlex
- W2883024539
- Cited by
- 419
- References
- 55
- Citations by year
- 2026: 39 · 2025: 51 · 2024: 66 · 2023: 36 · 2022: 65 · 2021: 55 · 2020: 60 · 2019: 41 · 2018: 6
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PROTACs, Bruton's tyrosine kinase, cereblon, E3 ubiquitin ligase, protein degradation, steric clashes, ternary complex formation, B cell maturation, undruggable targets
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Animals, Cells, Cultured, Ligands, Protein-Tyrosine Kinases, Thermodynamics, Polyubiquitin, Ubiquitin-Protein Ligases, Rats, Ubiquitination, Proteolysis
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