Design, synthesis, and biological evaluation of BRD4 degraders

Ding, Mengyuan; Shao, Yingying; Sun, Danwen; Meng, Suorina; Zang, Yi; Zhou, Yubo; Li, Jia; Lü, Wei; Zhu, Shulei

doi:10.1016/j.bmc.2022.117134

Cited by 11 publications

(14 citation statements)

References 37 publications

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“…Although a family of BET PROTAC degraders has been identified, the selectivity issue of BET PROTACs has not been fully addressed. Ding and Nowak designed and synthesized novel small-molecule BRD4 degraders 44 126 and 45 86 by using different linkages to conjugate JQ1 and E3 ligase ligands, respectively ( Fig. 39 ).…”

Section: Bromodomain and Extra-terminal (Bet) Domain-targeting Degradersmentioning

confidence: 99%

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Peng,

Hu,

Zeng

et al. 2024

Acta Pharmaceutica Sinica B

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Section: Bromodomain and Extra-terminal (Bet) Domain-targeting Degradersmentioning

confidence: 99%

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Peng,

Hu,

Zeng

et al. 2024

Acta Pharmaceutica Sinica B

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“… 133 From SAR studies, it is possible to verify that the incorporation of a phenyl group as a binding vector between the linker and ELM, in the 4‐position, reduced the activity of PROTAC. 133 On the other hand, if the vector is ethylenediamine, it generates a degrader (8b) that inhibits cell proliferation with IC 50 values between 3 and 27 nM, obtained through the induction of BRD4 degradation in a dose‐ and time‐dependent manner. 133 Replacing nitrogen with oxygen in the 4‐position leads to a reduction in PROTAC activity.…”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

“… 133 On the other hand, if the vector is ethylenediamine, it generates a degrader (8b) that inhibits cell proliferation with IC 50 values between 3 and 27 nM, obtained through the induction of BRD4 degradation in a dose‐ and time‐dependent manner. 133 Replacing nitrogen with oxygen in the 4‐position leads to a reduction in PROTAC activity. 133 …”

Section: Protacs Against Leukemia‐associated Targetsmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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“…A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1). 50,66–73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation 74–91 . Good drug‐like small‐molecule ligands for a E3 ligase system are still limited 92–97 .…”

Section: Introductionmentioning

confidence: 99%

“… 50 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation. 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 Good drug‐like small‐molecule ligands for a E3 ligase system are still limited. 92 , 93 , 94 , 95 , 96 , 97 Although more than 600 E3 ligases are encoded by human genome, only less than 10 E3 ligases were developed as ligands for the development of PROTAC degraders, including von Hippel‐Lindau (VHL), cereblon (CRBN), mouse double minute 2 (MDM2), cellular IAP1 (cIAP1), Kelch‐like ECH‐associated protein‐1 (KEAP1), DDB1‐cullin 4‐associated factor (DCAF), RING finger protein (RNF), aryl hydrocarbon receptor (AHR), and others (Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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Design, synthesis, and biological evaluation of BRD4 degraders

Cited by 11 publications

References 37 publications

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

PROTACs: A novel strategy for cancer drug discovery and development

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