作者: Cheng, Jia ; Yang, Yang ; Tao, Yanfang ; Jin, Zhongqin ; Yu, Juanjuan ; Ge, Haixia ; Li, Xue ; Shi, Chunxia ; Pan, Jian ; Hu, Shaoyan ; Bai, Huike

T cell acute lymphoblastic leukemia (T-ALL) is a rare lymphoblastic leukemia characterized by T lymphocyte heterogeneity and diverse genetic abnormalities, accounting for approximately 15% of childhood leukemias. BETd-246 serves as a tethering agent that links BETi-211 to thalidomide for the development of BET degraders. This compound has demonstrated superior efficacy in tumor treatment compared with traditional BET inhibitors. However, the anti-tumor effects and molecular mechanisms underlying the action of BETd-246 in T-ALL remain poorly understood. The aim of our study was to investigate the anti-tumor effects of BETd-246 and provide new insights into treatment strategies for T-ALL. In human T-ALL cell lines, BETd-246 induced degradation of BET proteins, particularly BRD4, at nanomolar concentrations. It effectively inhibited cell growth, disrupted the cell cycle, and promoted apoptosis in T-ALL cells in a concentration-dependent manner. The effects of BETd-246 were more pronounced than those of JQ1. In vivo experiments revealed that treatment with BETd-246 reduced proliferation and invasion of T-ALL cells and extended survival time in mouse models. RNA sequencing analysis indicated significant downregulation of T-cell receptor (TCR)-associated transmembrane adaptor 1 (TRAT1) expression in T-ALL cells treated with BETd-246. Knocking down TRAT1 resulted in increased growth inhibition and enhanced apoptosis within these cells. These findings suggest that TRAT1 plays a crucial role in mediating the effects of BETd-246 in T-ALL. Overall, our results indicate that BETd-246 is a promising therapeutic agent for treating this aggressive form of leukemia.

2025-08-28·CURRENT MEDICINAL CHEMISTRY

PROTACs Targeting Molecular Targets in Triple-Negative Breast Cancer

Article

作者: Hussain, Md Sadique ; Khan, Gyas ; Ahmad, Sarfaraz

Abstract::

Triple-Negative Breast Cancer (TNBC) is defined as a type of breast cancer having the absence of estrogen, progesterone, and human epidermal growth factor receptors. So far, chemotherapeutic drugs and immunotherapy have several issues, such as being resistant to treatment, being harmful to the body, and not being fully effective. Lately, PROTACs have been discovered to assist in the breakdown of difficult-to-target oncoproteins employing the ubiquitin-proteasome system. This review focuses on PROTACs used in TNBC, identifying BET proteins, SRC-1, PARP1, FAK, c-Myc, and CDKs as the primary molecular targets of PROTACs in this type of cancer. PROTACs can help overcome drug resistance, degrade harmful proteins over a prolonged period, and enhance the performance of these new therapies in clinical research. BETd-246, ND1-YL2, and pal-pom PROTACs have shown promise in reducing cancer progression and spread in TNBC. Additionally, the use of PROTACs to target EZH2, AR, and TRIM24 demonstrates that this approach offers great flexibility. While these findings are promising, it remains challenging to achieve better pharmacokinetics, maintain product stability, increase bioavailability, enhance selectivity, and prevent potential toxicity. New developments in PROTAC design and clinical results suggest that the strategy could lead to improved treatments for TNBC patients, helping them live longer and better.

2019-03-01·Neoplasia (New York, N.Y.)2区 · 医学

Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma

2区 · 医学

ArticleOA

作者: Harms, Paul W ; Choi, Jae Eun ; Wang, Rui ; Apel, Ingrid J ; Dlugosz, Andrzej A ; Jing, Xiaojun ; Verhaegen, Monique E ; Tien, Jean ; Yazdani, Mishaal ; Cao, Xuhong ; Cieślik, Marcin ; Wang, Yuping ; Juckette, Kristin ; Wang, Shaomeng ; Su, Fengyun ; Malik, Rohit ; Mangelberger, Doris ; Gurkan, Jonathan ; Chinnaiyan, Arul M ; Zhou, Bing ; Yazdani, Sahr

Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.

100 项与 BETd-246 相关的药物交易

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