Name: BETd-260
Brand: BOC Sciences
Rating: 5 (1 reviews)

Solubility

H2O : < 0.1 mg/mL (insoluble); DMSO : 25 mg/mL (31.29 mM; Need ultrasonic)

Storage

Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month

Shipping

Room temperature in continental US; may vary elsewhere

Synonyms

ZBC260; ZBC 260; ZBC-260; BETd-260; BETd 260; BETd260. 4-[(5-cyclopropyl-2-ethylpyrazol-3-yl)amino]-7-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]pentyl]-6-methoxy-9H-pyrimido[4,5-b]indole-2-carboxamide

InChI Key

UZXANFBIRSYHGO-UHFFFAOYSA-N

InChI

InChI=1S/C43H46N10O6/c1-5-53-34(20-30(50-53)25-13-14-25)46-39-37-27-19-33(58-4)28(36-22(2)51-59-23(36)3)18-31(27)45-38(37)48-40(49-39)42(56)44-17-8-6-7-10-24-11-9-12-26-29(24)21-52(43(26)57)32-15-16-35(54)47-41(32)55/h9,11-12,18-20,25,32H,5-8,10,13-17,21H2,1-4H3,(H,44,56)(H,47,54,55)(H2,45,46,48,49)

SMILES

CCN1C(=CC(=N1)C2CC2)NC3=NC(=NC4=C3C5=CC(=C(C=C5N4)C6=C(ON=C6C)C)OC)C(=O)NCCCCCC7=C8CN(C(=O)C8=CC=C7)C9CCC(=O)NC9=O

Mechanism

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

Binding Site: Binds the BET bromodomain acetyl-lysine pocket and recruited E3 ligase ligand site to support productive ternary complex formation.

Mechanism of Action: BETd-260 is designed for use in PROTAC or targeted protein degradation experiments directed toward BET bromodomain proteins, especially 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 BET Degradation: BETd-260 is utilized in research to effectively degrade BET proteins, which are critical regulators of gene expression. By harnessing the ubiquitin-proteasome system, this PROTAC facilitates the selective removal of BET proteins, providing a valuable tool for studying transcriptional regulation and epigenetic modifications.

• Targeted Protein Degradation in Cancer Research: BETd-260 is instrumental in investigating the role of BET proteins in oncogenesis. This PROTAC enables precise degradation of BET family members, allowing researchers to explore therapeutic strategies for cancer types where BET proteins are implicated in tumor growth and survival.

• Epigenetic Modulation via PROTACs: Researchers employ BETd-260 to probe the effects of BET protein degradation on epigenetic landscapes. By specifically targeting and degrading BET proteins, this PROTAC aids in understanding their contribution to chromatin remodeling and gene expression patterns, offering insights into epigenetic regulation mechanisms.

• Drug Discovery and Development: BETd-260 serves as a critical tool in the development of novel therapeutic agents targeting BET proteins. By facilitating the study of protein degradation pathways, this PROTAC aids in the identification of potential drug candidates and the elucidation of their mechanisms of action in preclinical research.

1. Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression

Bing Zhou, Jiantao Hu, Fuming Xu, Zhuo Chen, Longchuan Bai, Ester Fernandez-Salas, Mei Lin, Liu Liu, Chao-Yie Yang, Yujun Zhao, Donna McEachern, Sally Przybranowski, Bo Wen, Duxin Sun, Shaomeng Wang J Med Chem. 2018 Jan 25;61(2):462-481.doi: 10.1021/acs.jmedchem.6b01816.Epub 2017 Mar 24.

The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.

2. Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells

Huapeng Zhang, Gongquan Li, Yi Zhang, Jihua Shi, Bing Yan, Hongwei Tang, Sanyang Chen, Jiakai Zhang, Peihao Wen, Zhihui Wang, Chun Pang, Jie Li, Wenzhi Guo, Shuijun Zhang Front Oncol. 2020 Jan 14;9:1471.doi: 10.3389/fonc.2019.01471.eCollection 2019.

Background and Aim: Bromodomain and extraterminal domain (BET) family proteins are epigenetic regulators involved in human malignances. Targeting BET proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer therapeutics. BET proteins have been found to be overexpressed in HCC cells and tumor tissues. However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated anti-HCC activity of BETd-260, a BET-PROTAC molecule using in vitro and in vivo models. Methods: BETd-260-mediated anti-HCC activity was investigated by cell viability, apoptosis assays. Efficacy was examined with a cell lines-derived HCC xenograft model in mice. Anticancer mechanism was investigated by RT-PCR, western blotting and immunohistochemical staining. Results: BETd-260 potently suppressed cell viability and robustly induced apoptosis in HCC cells. BETd-260 reciprocally modulated the expression of several apoptotic genes in HCC cells, i.e., suppressing the expression of anti-apoptotic Mcl-1, Bcl-2, c-Myc, and X-linked inhibitor of apoptosis (XIAP), whereas increasing the expression of pro-apoptotic Bad. BETd-260 treatment led to disruption of mitochondrial membrane integrity, and triggered apoptosis via intrinsic signaling in HCC cells. BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice. Conclusion: Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC.

3. PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis

Chengcheng Shi, Huapeng Zhang, Penglei Wang, Kai Wang, Denghui Xu, Haitao Wang, Li Yin, Shuijun Zhang, Yi Zhang Cell Death Dis. 2019 Oct 25;10(11):815.doi: 10.1038/s41419-019-2022-2.

Targeting oncogenic proteins for degradation using proteolysis-targeting chimera (PROTAC) recently has drawn increasing attention in the field of cancer research. Bromodomain and extra-terminal (BET) family proteins are newly identified cancer-related epigenetic regulators, which have a role in the pathogenesis and progression of osteosarcoma. In this study, we investigated the in vitro and in vivo anti-osteosarcoma activity by targeting BET with a PROTAC molecule BETd-260. The results showed that BETd-260 completely depletes BET proteins and potently suppresses cell viability in MNNG/HOS, Saos-2, MG-63, and SJSA-1 osteosarcoma cell lines. Compared with BET inhibitors HJB-97 and JQ1, the activity of BETd-260 increased over 1000 times. Moreover, BETd-260 substantially inhibited the expression of anti-apoptotic Mcl-1, Bcl-xl while increased the expression of pro-apoptotic Noxa, which resulted in massive apoptosis in osteosarcoma cells within hours. In addition, pro-oncogenic protein c-Myc also was substantially inhibited by BETd-260 in the OS cells. Of note, BETd-260 induced degradation of BET proteins, triggered apoptosis in xenograft osteosarcoma tumor tissue, and profoundly inhibited the growth of cell-derived and patient-derived osteosarcoma xenografts in mice. Our findings indicate that BET PROTACs represent a promising therapeutic agent for human osteosarcoma.

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