Achieving clinical success with BET inhibitors as anti-cancer agents

British Journal of Cancer, Journal Year: 2021, Volume and Issue: 124(9), P. 1478 - 1490

Published: March 15, 2021

The transcriptional upregulation of oncogenes is a driving force behind the progression many tumours. However, until decade ago, concept 'switching off' these oncogenic pathways represented formidable challenge. Research has revealed that members bromo- and extra-terminal domain (BET) motif family are key activators networks in spectrum cancers; their function depends on recruitment to chromatin through two bromodomains (BD1 BD2). advent potent inhibitors BET proteins (BETi), which target either one or both bromodomains, represents an important step towards goal suppressing within Here, we discuss biology proteins, advances BETi design highlight potential biomarkers predicting activity. We also outline logic incorporating into combination therapies enhance its efficacy. suggest understanding mechanisms activity, defining predictive identifying synergies roadmap for clinical success using BETi.

Language: Английский

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Advances in targeting ‘undruggable’ transcription factors with small molecules

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(9), P. 669 - 688

Published: May 18, 2021

Language: Английский

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The BET family in immunity and disease

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Jan. 19, 2021

Innate immunity serves as the rapid and first-line defense against invading pathogens, this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain extraterminal domain (BET) family of proteins consists four conserved mammalian members (BRD2, BRD3, BRD4, BRDT) that regulate expression many immunity-associated genes pathways. In particular, in response to infection sterile inflammation, abnormally expressed or dysfunctional BETs are involved activation pattern recognition receptor (e.g., TLR, NLR, CGAS) pathways, thereby linking chromatin machinery innate under disease pathological conditions. Mechanistically, BET controls transcription a wide range proinflammatory immunoregulatory by recognizing acetylated histones (mainly H3 H4) recruiting factors RELA) elongation complex P-TEFb) chromatin, promoting phosphorylation RNA polymerase II subsequent initiation elongation. This review covers accumulating data about roles immunity, discusses attractive prospect manipulating new treatment for disease.

Language: Английский

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Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Nature Chemical Biology, Journal Year: 2021, Volume and Issue: 17(11), P. 1157 - 1167

Published: Oct. 21, 2021

Language: Английский

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BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2167 - 2182.e22

Published: March 18, 2021

Language: Английский

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Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2576 - 2607

Published: Feb. 17, 2021

Heterobifunctional compounds that direct the ubiquitination of intracellular proteins in a targeted manner via co-opted ubiquitin ligases have enormous potential to transform field medicinal chemistry. These chimeric molecules, often termed proteolysis-targeting chimeras (PROTACs) chemical literature, enable controlled degradation specific their direction cellular proteasome. In this report, we describe second phase our research focused on exploring antibody–drug conjugates (ADCs), which incorporate BRD4-targeting degrader entities. We employ new BRD4-binding fragment construction ADC payloads is significantly more potent than corresponding entity utilized initial studies. The resulting BRD4-degrader antibody exhibit and antigen-dependent BRD4 antiproliferation activities cell-based experiments. Multiple ADCs bearing also strong, antitumor efficacy mouse xenograft assessments several different tumor models.

Language: Английский

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Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2534 - 2575

Published: Feb. 17, 2021

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) related chimeric molecules that effect intracellular degradation target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these entities are relatively large compounds often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation such monoclonal antibodies using technologies originally developed for cytotoxic payloads so as provide alternate delivery options novel agents. In this report, we describe first phase our systematic development antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting degrader entities. demonstrate antigen-dependent PC3-S1 prostate cancer cells along with on MYC transcription BRD4 levels. These experiments culminate identification one conjugate, exhibits antiproliferation effects LNCaP cells.

Language: Английский

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Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2419 - 2435

Published: Feb. 22, 2021

Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones nonhistone via tandem bromodomains regulate chromatin dynamics, cellular processes, disease procession. Thus targeting BET is a promising strategy for treating various diseases, especially malignant tumors chronic inflammation. Many pan-BET small-molecule inhibitors have been described, some of them are clinical evaluation. Nevertheless, the limited efficacy current also evident has inspired development new technologies to improve their outcomes minimize unwanted side effects. In this Review, we summarize latest protein characteristics biological functions BRD4 as an example proteins, analyze status preclinical resistance mechanisms, discuss recent advances BRD4-selective inhibitors, dual-target proteolysis chimera degraders, protein–protein interaction inhibitors.

Language: Английский

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Cancer epigenetics: from laboratory studies and clinical trials to precision medicine

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 15, 2024

Abstract Epigenetic dysregulation is a common feature of myriad human diseases, particularly cancer. Defining the epigenetic defects associated with malignant tumors has become focus cancer research resulting in gradual elucidation cell regulation. In fact, most stages tumor progression, including tumorigenesis, promotion, and recurrence are accompanied by alterations, some which can be reversed drugs. The main objective therapy era personalized precision medicine to detect biomarkers improve risk assessment, diagnosis, targeted treatment interventions. Rapid technological advancements streamlining characterization molecular changes cancers have propelled drug development. This review summarizes mechanisms discusses past present examples inhibitors diagnosis treatment, an emphasis on development enzyme or final part, prospect precise considered based better understanding abnormalities

Language: Английский

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Bromodomain and extraterminal (BET) proteins: biological functions, diseases and targeted therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Nov. 6, 2023

BET proteins, which influence gene expression and contribute to the development of cancer, are epigenetic interpreters. Thus, inhibitors represent a novel form anticancer treatment. Although preliminary clinical trials have shown potential inhibitors, it appears that these drugs limited effectiveness when used alone. Therefore, given monotherapeutic activity their use in combination with other warrants attention, including meaningful variations pharmacodynamic among chosen drug combinations. In this paper, we review function preclinical justification for protein targeting recent advances small-molecule trial findings. We elucidate inhibitor resistance mechanisms, shed light on associated adverse events, investigate combining diverse therapeutic agents, present comprehensive compilation synergistic treatments involving provide an outlook future prospects as potent antitumor agents. conclude by suggesting innovative next-generation agents holds great advancing effective proteins promising strategy.

Language: Английский

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