Impact of target warhead and linkage vector on inducing protein degradation: comparison of Bromodomain and Extra-Terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds

Kwok Ho Chan, Michael Zengerle, Andrea Testa, Alessio Ciulli (Lead / Corresponding author)

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Abstract

The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs, and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders is anticipated to have wide future applicability.
Original languageEnglish
Pages (from-to)504-513
Number of pages10
JournalJournal of Medicinal Chemistry
Volume61
Issue number2
Early online date8 Jun 2017
DOIs
Publication statusPublished - 25 Jan 2018

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WEB 2086
Proteolysis
Ligands
Ubiquitin-Protein Ligases
Myeloid Cells
Structure-Activity Relationship
Acute Myeloid Leukemia
4-(1-acetyl-4-((4-chlorophenyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid
1,2,3,4-tetrahydroquinoline
Cell Line

Keywords

  • protein degradation
  • PROTACs
  • bromodomain
  • cooperativity
  • acute myeloid leukemia

Cite this

@article{d56f518713034abbbe4f2e0144f4839d,
title = "Impact of target warhead and linkage vector on inducing protein degradation: comparison of Bromodomain and Extra-Terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds",
abstract = "The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs, and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders is anticipated to have wide future applicability.",
keywords = "protein degradation, PROTACs, bromodomain, cooperativity, acute myeloid leukemia",
author = "Chan, {Kwok Ho} and Michael Zengerle and Andrea Testa and Alessio Ciulli",
note = "This work was supported by the European Research Council (ERC-2012-StG-311460 DrugE3CRLs Starting Grant to A.C.); the UK Biotechnology and Biological Sciences Research Council (BBSRC grant BB/J001201/2 to A.C.); the European Commission (H2020-MSCA-IF-2014-655516 Marie Skłodowska-Curie Actions Individual Fellowship to K-H.C.); and the Wellcome Trust (Strategic Awards 100476/Z/12/Z for biophysics and drug discovery to the Division of Biological Chemistry and Drug Discovery).",
year = "2018",
month = "1",
day = "25",
doi = "10.1021/acs.jmedchem.6b01912",
language = "English",
volume = "61",
pages = "504--513",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

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TY - JOUR

T1 - Impact of target warhead and linkage vector on inducing protein degradation

T2 - comparison of Bromodomain and Extra-Terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds

AU - Chan, Kwok Ho

AU - Zengerle, Michael

AU - Testa, Andrea

AU - Ciulli, Alessio

N1 - This work was supported by the European Research Council (ERC-2012-StG-311460 DrugE3CRLs Starting Grant to A.C.); the UK Biotechnology and Biological Sciences Research Council (BBSRC grant BB/J001201/2 to A.C.); the European Commission (H2020-MSCA-IF-2014-655516 Marie Skłodowska-Curie Actions Individual Fellowship to K-H.C.); and the Wellcome Trust (Strategic Awards 100476/Z/12/Z for biophysics and drug discovery to the Division of Biological Chemistry and Drug Discovery).

PY - 2018/1/25

Y1 - 2018/1/25

N2 - The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs, and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders is anticipated to have wide future applicability.

AB - The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation, and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs, and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders is anticipated to have wide future applicability.

KW - protein degradation

KW - PROTACs

KW - bromodomain

KW - cooperativity

KW - acute myeloid leukemia

U2 - 10.1021/acs.jmedchem.6b01912

DO - 10.1021/acs.jmedchem.6b01912

M3 - Article

C2 - 28595007

VL - 61

SP - 504

EP - 513

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -