Modular PROTAC design for the degradation of oncogenic BCR-ABL
Open accessAbstract
Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.
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Over 60 proteins of interest from diverse protein families and structural classes have been successfully degraded using a TPD strategy.
“Over 60 POIs from diverse protein families and structural classes have been successfully degraded using a TPD strategy.”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Lai et al., 2016
The pairing of VHL versus CRBN for a given target can result in different degradation efficiencies.
“the pairing of VHL versus CRBN for a given target can result in different degradation efficiencies49, as was first observed when targeting the fusion oncogene BCR–ABL by PROTACs118.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [118]
A major advantage of VHL-based PROTACs is their target-specificity.
“A major advantage of VHL-based PROTACs is their target-specificity [44, 53].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [44]
Using the same BCR-ABL ligands, CRBN-based PROTACs degraded both BCR-ABL and c-ABL, whereas VHL-based PROTACs could only degrade c-ABL.
“using the same BCR-ABL ligands, the CRBN-based PROTACs degraded both BCR-ABL and c-ABL, whereas VHL-based PROTACs could only degrade c-ABL [44].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [44]
PROTACs against BRD4, BTK, BCR-ABL and CDK-6 have shown efficacy in leukemia.
“For example, PROTACs against BRD4, BTK, BCR-ABL and CDK-6 etc. have shown efficacy in leukemia [22, 44, 58, 60], whereas AR, ER, FAK, P38 PROTACs have been developed against different solid tumors [13, 49, 51, 104] (Table 1).”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [44]
VHL-PROTACs binding BCR-Abl inhibited downstream signalling, but protein levels remained unchanged.
“While binding of the PROTACs to BCR–Abl still inhibited downstream signalling, protein levels remained unchanged with any of the tested VHL-PROTACs.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [86]
Dasatinib-VHL PROTAC degraded c-Abl at 1 μM, but higher concentrations left c-Abl protein levels unaffected.
“Interestingly, c-Abl could be degraded with a dasatinib–VHL PROTAC at 1 µM, however, higher concentrations left c-Abl protein levels unaffected [86].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [86]
Bosutinib- and dasatinib-pomalidomide PROTACs efficiently degrade both BCR-Abl and c-Abl at around 100 nM concentrations, and the dasatinib-pomalidomide PROTAC reduces cell viability with a 1000-fold higher efficiency over non-BCR-Abl driven cell lines.
“In contrast, both bosutinib- and dasatinib–pomalidomide PROTACs were able to efficiently degrade both BCR–Abl and c-Abl at around 100 nM concentrations and the dasatinib–pomalidomide PROTAC was efficient at reducing cell viability with a 1000-fold higher efficiency over non-BCR–Abl driven cell lines [86].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [86]
Even among degradable targets, the choice of E3 ligase pairing appears critical.
“Indeed, even among degradable targets, the choice of E3 pairing appears critical 10 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [10]
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- Authors
- Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crews, Craig M.
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2015-11-23
- Volume
- 55
- Issue
- 2
- Pages
- 807-810
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC4733637
- OpenAlex
- W2176682109
- Cited by
- 618
- References
- 22
- Citations by year
- 2026: 31 · 2025: 52 · 2024: 65 · 2023: 63 · 2022: 77 · 2021: 61 · 2020: 89 · 2019: 63 · 2018: 51 · 2017: 47 · 2016: 16 · 2015: 1
- FWCI
- 16.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (T32GM067543, R35CA197589, R01AI084140, MTSP TG-T32GM007205)
- EMBO (ALTF-1102-2014)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, BCR-ABL, c-Abl, protein degradation, E3 ubiquitin ligase, cereblon, VHL, ubiquitination, proteasome
- MeSH terms
- Cell Line, Humans, Fusion Proteins, bcr-abl, Cell Line, Tumor, Proteolysis
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