Name: QCA570
Brand: BOC Sciences
Rating: 5 (1 reviews)

Solubility

10 mM in DMSO;H2O : ≥ 150 mg/mL

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Shipping

Room temperature in continental US; may vary elsewhere

Synonyms

QCA570; QCA-570; QCA 570; 3-(4-(5-(4-((3-Benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]-triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)pent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

InChI Key

RTVTYLRQKKDYMQ-UHFFFAOYSA-N

InChI

InChI=1S/C39H33N7O4S/c1-25-42-43-35-24-50-23-32-30(19-26-9-4-2-5-10-26)34(51-39(32)46(25)35)16-14-27-20-40-44(21-27)18-7-3-6-11-28-12-8-13-29-31(28)22-45(38(29)49)33-15-17-36(47)41-37(33)48/h2,4-5,8-10,12-13,20-21,33H,3,7,15,17-19,22-24H2,1H3,(H,41,47,48)

SMILES

CC1=NN=C2N1C3=C(COC2)C(=C(S3)C#CC4=CN(N=C4)CCCC#CC5=C6CN(C(=O)C6=CC=C5)C7CCC(=O)NC7=O)CC8=CC=CC=C8

Mechanism

Target: Targets BET bromodomain proteins, primarily BRD4, BRD3, and BRD2 for experimental targeted protein degradation studies.

Binding Site: Binds the BET acetyl-lysine pocket and cereblon thalidomide-binding domain to support productive ternary complex formation.

Mechanism of Action: QCA570 is designed for use in PROTAC or targeted protein degradation experiments directed toward BET bromodomain proteins, primarily BRD4, BRD3, and BRD2. The bifunctional molecule links a target-recognition element to cereblon, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated Kinase Degradation: QCA570 is designed for the targeted degradation of kinases, offering a precise approach to modulate kinase-driven signaling pathways. This application is pivotal for studying the regulatory roles of kinases in cellular processes and for validating potential therapeutic targets in oncology and inflammatory diseases.

• Targeted Degradation in Cancer Research: Utilizing QCA570 in cancer models facilitates the selective degradation of oncogenic proteins. This approach allows researchers to dissect the functional consequences of protein loss, providing insights into tumorigenesis and aiding in the identification of novel cancer treatment strategies.

• Protein Homeostasis Studies: QCA570 serves as a valuable tool for investigating the mechanisms of protein homeostasis through targeted protein degradation. By selectively degrading specific proteins, researchers can explore the dynamic balance of protein synthesis and degradation, contributing to our understanding of cellular proteostasis networks.

• Development of Degradation Assays: The application of QCA570 in developing degradation assays enables the quantification and analysis of protein degradation kinetics. This is essential for optimizing PROTAC design and enhancing the efficacy of targeted protein degradation strategies in various biological settings.

1. Lethal activity of BRD4 PROTAC degrader QCA570 against bladder cancer cells

Qiang Wang, Baohu Li, Wenkai Zhang, Zhuoyue Li, Bo Jiang, Sichuan Hou, Shumin Ma, Chong Qin Front Chem. 2023 Jan 17;11:1121724.doi: 10.3389/fchem.2023.1121724.eCollection 2023.

Bladder cancer is the most common malignancy of the urinary system. Efforts to identify innovative and effective therapies for bladder cancer are urgently needed. Recent studies have identified the BRD4 protein as the critical factor in regulation of cell proliferation and apoptosis in bladder cancer, and it shows promising potential for pharmacologic treatment against bladder cancer. In this study, we have evaluated the biological function of QCA570, a novel BET degrader, on multiple bladder cancer cells and explore its underlying mechanisms. QCA570 potently induces degradation of BRD4 protein at nanomolar concentrations, with a DC50 of ~ 1 nM. It decreases EZH2 and c-MYC levels by transcriptional suppression and protein degradation. Moreover, the degrader significantly induces cell apoptosis and cycle arrest and shows antiproliferation activity against bladder cancer cells. These findings support the potential efficacy of QCA570 on bladder cancer.

2. The novel BET degrader, QCA570, is highly active against the growth of human NSCLC cells and synergizes with osimertinib in suppressing osimertinib-resistant EGFR-mutant NSCLC cells

Chaoyuan Liu, Luxi Qian, Karin A Vallega, Guangzhi Ma, Dan Zong, Luxiao Chen, Shaomeng Wang, Suresh R Ramalingam, Zhaohui Qin, Shi-Yong Sun Am J Cancer Res. 2022 Feb 15;12(2):779-792.eCollection 2022.

Lung cancer remains the leading cause of cancer deaths worldwide despite advances in knowledge in cancer biology and options of various targeted therapies. Efforts in identifying innovative and effective therapies are still highly appreciated. Targeting bromodomain and extra terminal (BET) proteins that function as epigenetic readers and master transcription coactivators is now a potential cancer therapeutic strategy. The current study evaluates the therapeutic efficacies of the novel BET degrader, QCA570, in lung cancer and explores its underlying mechanisms. QCA570 at low nanomolar ranges effectively decreased the survival of a panel of human lung cancer cell lines with induction of apoptosis in vitro. As expected, it potently induced degradation of BET proteins including BRD4, BRD3 and BRD2. Moreover, it potently decreased Mcl-1 levels due to transcriptional suppression and protein degradation; this event is critical for mediating apoptosis induced by QCA570. Moreover, QCA570 synergized with osimertinib in suppressing the growth of osimertinib-resistant cells in vitro and in vivo, suggesting potential in overcoming acquired resistance to osimertinib. These preclinical findings support the potential of QCA570 in treatment of lung cancer either as a single agent or in combination with others.

3. 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

Chong Qin, Yang Hu, Bing Zhou, Ester Fernandez-Salas, et al. J Med Chem. 2018 Aug 9;61(15):6685-6704.doi: 10.1021/acs.jmedchem.8b00506.Epub 2018 Jul 18.

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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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂