2093386-40-2Relevant academic research and scientific papers
Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91
Hanafi, Maha,Chen, Xinde,Neamati, Nouri
, p. 1626 - 1648 (2021/02/27)
Napabucasin, undergoing multiple clinical trials, was reported to inhibit the signal transducer and transcription factor 3 (STAT3). To better elucidate its mechanism of action, we designed a napabucasin-based proteolysis targeting chimera (PROTAC), XD2-149 that resulted in inhibition of STAT3 signaling in pancreatic cancer cell lines without inducing proteasome-dependent degradation of STAT3. Proteomics analysis of XD2-149 revealed the downregulation of the E3 ubiquitin-protein ligase ZFP91. XD2-149 degrades ZFP91 with DC50 values in the nanomolar range. The cytotoxicity of XD2-149 was significantly, but not fully, reduced with ZFP91 knockdown providing evidence for its multi-targeted mechanism of action. The NQO1 inhibitor, dicoumarol, rescued the cytotoxicity of XD2-149 but not ZFP91 degradation, suggesting that the NQO1-induced cell death is independent of ZFP91. ZFP91 plays a role in tumorigenesis and is involved in multiple oncogenic pathways including NF-κB and HIF-1α.
Design, Synthesis, and Evaluation of Potent, Selective, and Bioavailable AKT Kinase Degraders
Cahuzac, Kaitlyn M.,Chen, Xian,Jin, Jian,Liu, Jing,Parsons, Ramon E.,Shen, Yudao,Wang, Li,Xie, Ling,Xu, Jia,Yu, Xufen
, p. 18054 - 18081 (2021/12/13)
The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.
Designing an eEF2K-Targeting PROTAC small molecule that induces apoptosis in MDA-MB-231 cells
Liu, Yao,Zhen, Yongqi,Wang, Guan,Yang, Gaoxia,Fu, Leilei,Liu, Bo,Ouyang, Liang
, (2020/07/27)
Eukaryotic elongation factor 2 kinase (eEF2K) is a key α-kinase that negatively regulates the extension step of protein synthesis, which consumes most of the energy and amino acids required for protein synthesis. Studies have found that eEF2K protein is related to the breast cancer. However, existing inhibitor effect has not achieved the desired effect in cancer therapy. Proteolysis target chimeric (PROTAC) technology is uses proteasome to degrade target protein to achieve the purpose of inhibiting tumour cell growth. Here, we reported that the use of PROTAC strategy in combining with star eEF2K inhibitor A484954 and its potential derivatives. Consequently, candidate compound 11l was found to degrade eEF2K and induce apoptosis in human breast carcinoma MDA-MB-231 cells. Together, these findings demonstrate that our eEF2K-targeting PROTAC small molecule would be a potential new strategy for future breast cancer therapy.
Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression
Zhou, Bing,Hu, Jiantao,Xu, Fuming,Chen, Zhuo,Bai, Longchuan,Fernandez-Salas, Ester,Lin, Mei,Liu, Liu,Yang, Chao-Yie,Zhao, Yujun,McEachern, Donna,Przybranowski, Sally,Wen, Bo,Sun, Duxin,Wang, Shaomeng
, p. 462 - 481 (2018/02/07)
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.
