BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein–protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective ...

Drug Discovery Targeting Bromodomain-Containing Protein 4.

Proteins of the bromodomain and extra-terminal (BET) family are epigenetics “readers” and promising therapeutic targets for cancer and other human diseases We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules QCA570 is the most potent and efficacious BET degrader reported to date

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Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Bromodomain-containing protein 4 (Brd4) plays an important role in mediating the expression of genes involved in cancers and non-cancer diseases such as inflammatory diseases and acute heart failure. Inactivating Brd4 or downregulating its expression inhibits cancer development, leading to the current interest in Brd4 as a promising anticancer drug target. Numerous Brd4 inhibitors have been studied in recent years and some of them are currently in various phases of clinical trials. Recently, selective degradation of target proteins by small bifunctional molecules (PROTACs) has emerged as an attractive drug discovery approach owing to the advantages it could offer over traditional small-molecule inhibitors. A number of Brd4 degraders have been reported and showed more efficient anticancer activities than just protein inhibition. In this review, we will discuss recent findings in the discovery and development of small-molecule inhibitors and degraders that target Brd4 as a potential anticancer agent.

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Targeting Brd4 for cancer therapy: inhibitors and degraders.

Cobalt-Catalyzed Direct Carbonylative Synthesis of Free (NH)-Benzo[cd]indol-2(1H)-ones from Naphthylamides.

Introduction: Docking and structure-based virtual screening (VS) have been standard approaches in structure-based design for over two decades. However, our understanding of the limitations, potential, and strength of these techniques has enhanced, raising expectations. Areas covered: Based on a survey of reports in the past five years, we assess whether VS: (1) predicts binding poses in agreement with crystallographic data (when available); (2) is a superior screening tool, as often claimed; (3) is successful in identifying chemical scaffolds that can be starting points for subsequent lead optimization cycles. Data shows that knowledge of the target and its chemotypes in postprocessing lead to viable hits in early drug discovery endeavors. Expert opinion: VS is capable of accurate placements in the pocket for the most part, but does not consistently score screening collections accurately. What matters is capitalization on available resources to get closer to a viable lead or optimizable series. Integration of approaches, subjective hit selection guided by knowledge of the receptor or endogenous ligand, libraries driven by experimental guides, validation studies to identify the best docking/scoring that reproduces experimental findings, constraints regarding receptor-ligand interactions, thoroughly designed methodologies, and predefined cutoff scoring criteria strengthen VS's position in pharmaceutical research.

The compromise of virtual screening and its impact on drug discovery

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective ...

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation

The invention relates to the technical field of chemical medicines and particularly discloses a 2-oxo-1,2-dihydrobenzo[cd]indole compound and an application thereof. The compound, as well as pharmaceutically acceptable salts, isomers, racemes, prodrugs, co-crystallized compounds, hydrates and solvates thereof, can effectively inhibit a BET bromodomain acceptor, so that the compound can be used for preparing medicines for treating cancer, cell proliferation disorders, inflammation diseases, autoimmune diseases, sepsis and virus infection.

2-oxo-1,2-dihydrobenzo[cd]indole compound and application thereof

The invention relates to the technical field of chemical medicines, and particularly discloses a 2-oxo-1, 2-dihydrobenzo [cd] indole compound. The compound and the pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystallization compound, hydrate and solvate of the compound can effectively inhibit a BET bromodomain receptor, and can be used for preparing a medicine for treating cancers, cell proliferation disorders, inflammatory diseases, autoimmune diseases, septicemia and virus infection.

Liu Zhaoxuan

Papers

Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation

2-oxo-1,2-dihydrobenzo[cd]indole compound and application thereof

2-oxo-1, 2-dihydrobenzo [cd] indole compound