Abstract
PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line
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Cell Survival / drug effects
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Humans
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Leukemia / drug therapy
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Leukemia / genetics
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Leukemia / metabolism*
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Lysine / chemistry
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Lysine / genetics
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Lysine / metabolism
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Models, Molecular
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Conformation
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Proteolysis
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Proto-Oncogene Proteins c-bcl-2 / chemistry
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Ubiquitin-Conjugating Enzymes / chemistry
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Ubiquitin-Conjugating Enzymes / metabolism
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
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bcl-X Protein / chemistry
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Antineoplastic Agents
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BCL2 protein, human
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BCL2L1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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Small Molecule Libraries
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bcl-X Protein
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Ubiquitin-Conjugating Enzymes
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Proteasome Endopeptidase Complex
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Lysine