959150-64-2Relevant academic research and scientific papers
In pursuit of a selective hepatocellular carcinoma therapeutic agent: Novel thalidomide derivatives with antiproliferative, antimigratory and STAT3 inhibitory properties
Nutt, Michael J.,Yee, Yeung Sing,Buyan, Amanda,Andrewartha, Neil,Corry, Ben,Yeoh, George C.T.,Stewart, Scott G.
, (2021/03/30)
Advanced stage liver cancer is predominantly treated with the multi-kinase inhibitor sorafenib; however, this therapeutic agent lacks selectivity in its cytotoxic actions and is associated with poor survival outcomes. Herein we report the design and preparation of several thalidomide derivatives, including a variety of novel thioether-containing forms that are especially rare in the literature. Importantly, two of the derivatives described are potent antiproliferative agents with dose-dependent selectivity for tumorigenic liver progenitor cells (LPC) growth inhibition (up to 36% increase in doubling time at 10 μM) over non-tumorigenic cells (no effect at 10 μM). Furthermore, these putative anti-liver cancer agents were also found to be potent inhibitors of tumorigenic LPC migration. This report also describes these derivatives’ effects on several key signalling pathways in our novel liver cell lines by immunofluorescence and AlphaLISA assays. Aryl thioether derivative 7f significantly reduced STAT3 phosphorylation (23%) and its nuclear localisation (16%) at 10 μM in tumorigenic LPCs, implicating the IL-6/JAK/STAT3 axis is central in the mode of action of our derivatives.
Proteolysis-Targeting Chimera (PROTAC) Modification of Dovitinib Enhances the Antiproliferative Effect against FLT3-ITD-Positive Acute Myeloid Leukemia Cells
Cao, Sheng,Dong, Zhiqiang,Li, Chen,Li, Ming,Li, Xuechun,Liu, Ning,Liu, Yulin,Ma, Lan,Wang, Ruonan,Wang, Xiaoji,Wei, Mingming,Yang, Cheng,Yang, Guang,Yao, Yuhong
supporting information, p. 16497 - 16511 (2021/11/16)
Acute myeloid leukemia (AML) refers to one of the most lethal blood malignancies worldwide. FLT3-ITD mutation is recognized as the most common one that predicted a poorer prognosis. There have been many prominent FLT3-ITD inhibitors approved by the FDA for clinical therapies. However, as impacted by undesirable off-target effects, differentiated metabolic issues, and clinical drug resistance problems, it remains challenging to discover alternative and promising solutions for treating FLT3-ITD+ AML. In this study, dovitinib was chemically modified and converted into CRBN-recruiting PROTACs. Two active compounds were identified, which showed enhanced antiproliferative effects against FLT3-ITD+ AML cells, both in vitro and in vivo. As demonstrated from further biological evaluation, the compounds could induce the degradation of the FLT3-ITD and KIT proteins in a ubiquitin-proteasome-dependent manner and completely block their downstream signaling pathway. The findings of this study would provide another promising strategy to develop novel therapies for FLT3-ITD+ AML.
Protein hydrolysis target chimera and pharmaceutical composition and application thereof
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Paragraph 0025-0027; 0038-0039; 0071-0074, (2021/10/27)
The invention discloses a protein hydrolysis target chimera which can effectively induce degradation of FLT3-ITD in MOM - 13-MV - 4 - 11 positive cells FLT3 and ITD in a dose-dependent manner and a time-dependent manner. The in vivo study shows that the internal CD45 of the acute myelogenous leukemia mouse can be remarkably reduced. + The positive cell level shows a better treatment effect on acute myelogenous leukemia.
In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)
Wang, Yubo,Zhou, Yuanyuan,Cao, Sheng,Sun, Yue,Dong, Zhiqiang,Li, Chen,Wang, Haoran,Yao, Yuhong,Yu, Haiyan,Song, Xiangyi,Li, Ming,Wang, Jiefu,Wei, Mingming,Yang, Guang,Yang, Cheng
supporting information, (2021/04/12)
Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.
Proteolysis targeting chimera and application thereof
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Paragraph 0093-0095, (2021/07/14)
The invention provides a proteolysis targeting chimera and application thereof. According to a technical scheme in the invention, a novel PROTAC degradation agent compound 21a is developed on the basis of a BMS-37 small molecule. The novel PROTAC degradation agent compound 21a is an example of degrading membrane proteins on the basis of a ligand binding to the extracellular domain of a PD-L1 protein, and can effectively degrade PD-L1 in various malignant tumor cells. In-vivo research results show that after treatment with the compound 21a, the compound 21a can significantly reduce the level of the PD-L1 in tumors, promote infiltration of CD8T cells and significantly inhibit growth of mouse colorectal cancer MC-38 cells. The PROTAC molecule is expected to be one of novel and alternative strategies for cancer immunotherapy.
New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles
Stewart, Scott G.,Braun, Carlos J.,Ng, Sze-Ling,Polomska, Marta E.,Karimi, Mahdad,Abraham, Lawrence J.
experimental part, p. 650 - 662 (2010/04/26)
A library of new thalidomide C4/5 analogues containing either a phenyl or alkyne tether were synthesized using Sonogashira or Suzuki cross coupling reactions from their aryl halogenated precursors. All thalidomide analogues were tested for their ability to inhibit the expression of the proinflammatory cytokine Tumor Necrosis Factor (TNF). More explicitly the use of a novel reporter system utilizing the promoter region of the TNF gene in a human T-cell line provided a rapid and effective measure of NFκB transcriptional activity. Several compounds either containing either an aryl-isobutyl or aryl-isopropoxy group were the most effective in inhibiting TNF expression, and were several times more active than thalidomide itself. Five of the more active derivatives indicated an apoptotic response while one of these compounds, containing an aldehyde tether, showed possible influence of cell cycling effects.
Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling
Stewart, Scott G.,Spagnolo, Daniel,Polomska, Marta E.,Sin, Melvin,Karimi, Mahdad,Abraham, Lawrence J.
, p. 5819 - 5824 (2008/03/13)
A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively. Crown Copyright
