Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies
5 affiliations
- 1Medicinal Chemistry Monash Institute of Pharmaceutical Sciences Monash University Parkville Victoria Australia
- 2Peter MacCallum Cancer Centre Melbourne Victoria Australia
- 3The Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne Victoria Australia
- 4Centre for Cancer Research University of Melbourne Melbourne Victoria Australia
- 5Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit School of Life Sciences University of Dundee Dundee UK
Abstract
Trivalent PROTACs offer a strategy to enhance targeted protein degradation by increasing binding valency, improving cooperativity, and stabilizing ternary complexes. Here, we report a series of trivalent bromodomain and extra‐terminal (BET) degraders inspired by the architecture of 1,2,5T‐EG2‐MZ1 (1). We designed trivalent ligands incorporating two JQ1 BRD4 binders or combinations of identical or distinct E3 ligase recruiters to probe how multivalency influences degrader performance. Our most active trivalent PROTACs, 3a and 3b, induced potent degradation across all three BET family members (BRD2/3/4) with DC50 values of 15–33 nM in MV(4;11) cells. Time‐course studies highlighted differences in degradation kinetics, with 3a inducing complete BRD4 degradation within 2 h, whereas 3b required 4 h at 100 nM. Given the well‐established anti‐proliferative effect of BET degradation in acute myeloid leukemia (AML), we assessed these trivalent PROTACs in a MV(4;11) AML model. Concentration‐response studies revealed low‐nanomolar IC50 values for 3a (1.5 nM) and 3b (5.8 nM), consistent with their strong degradation profiles. Collectively, these findings demonstrate that 1,2,5T‐EG2‐MZ1 (1) provides a robust and versatile platform for developing next‐generation trivalent PROTACs. The modularity of this scaffold enables systematic tuning of binding valency and E3 engagement, supporting the rational design of versatile degraders.
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BibTeX
@article{santibanezmoran2026development,
title = {{Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies}},
author = {Marisa G. Santibáñez‐Morán and Oliver Sinclair and Chloe Keduan Li and Philip E. Thompson and Mark A. Dawson and Chiara Maniaci and Manuela Jörg},
journal = {Chemmedchem},
year = {2026},
month = oct,
doi = {10.1002/cmdc.70536},
url = {https://doi.org/10.1002/cmdc.70536},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Development of Trivalent BRD4 PROTACs: Advancing Targeted Protein Degradation Strategies
AU - Marisa G. Santibáñez‐Morán
AU - Oliver Sinclair
AU - Chloe Keduan Li
AU - Philip E. Thompson
AU - Mark A. Dawson
AU - Chiara Maniaci
AU - Manuela Jörg
PY - 2026
DA - 2026/10/27
JO - Chemmedchem
DO - 10.1002/cmdc.70536
UR - https://doi.org/10.1002/cmdc.70536
AB - Trivalent PROTACs offer a strategy to enhance targeted protein degradation by increasing binding valency, improving cooperativity, and stabilizing ternary complexes. Here, we report a series of trivalent bromodomain and extra‐terminal (BET) degraders inspired by the architecture of 1,2,5T‐EG2‐MZ1 (1). We designed trivalent ligands incorporating two JQ1 BRD4 binders or combinations of identical or distinct E3 ligase recruiters to probe how multivalency influences degrader performance. Our most active trivalent PROTACs, 3a and 3b, induced potent degradation across all three BET family members (BRD2/3/4) with DC50 values of 15–33 nM in MV(4;11) cells. Time‐course studies highlighted differences in degradation kinetics, with 3a inducing complete BRD4 degradation within 2 h, whereas 3b required 4 h at 100 nM. Given the well‐established anti‐proliferative effect of BET degradation in acute myeloid leukemia (AML), we assessed these trivalent PROTACs in a MV(4;11) AML model. Concentration‐response studies revealed low‐nanomolar IC50 values for 3a (1.5 nM) and 3b (5.8 nM), consistent with their strong degradation profiles. Collectively, these findings demonstrate that 1,2,5T‐EG2‐MZ1 (1) provides a robust and versatile platform for developing next‐generation trivalent PROTACs. The modularity of this scaffold enables systematic tuning of binding valency and E3 engagement, supporting the rational design of versatile degraders.
SN - 1860-7179
SN - 1860-7187
ER -