排序方式: 共有11条查询结果,搜索用时 15 毫秒
1.
Laura Sinatra Jan J. Bandolik Dr. Martin Roatsch Melf Sönnichsen Dr. Clara T. Schoeder Dr. Alexandra Hamacher Andrea Schöler Prof. Dr. Arndt Borkhardt Prof. Dr. Jens Meiler Dr. Sanil Bhatia Prof. Dr. Matthias U. Kassack Prof. Dr. Finn K. Hansen 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(50):22681-22687
2.
PROTACs employ the proteosome-mediated proteolysis via E3 ligase and recruit the natural protein degradation machinery to selectively degrade the cancerous proteins. Herein, we have designed and synthesized heterobifunctional small molecules that consist of different linkers tethering KRIBB11, a HSF1 inhibitor, with pomalidomide, a commonly used E3 ligase ligand for anticancer drug development. 相似文献
3.
Dr. Thomas G. Hayhow Rachel E. A. Borrows Dr. Coura R. Diène Gary Fairley Dr. Charlene Fallan Dr. Shaun M. Fillery Dr. James S. Scott Dr. David W. Watson 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(70):16818-16823
A palladium-catalysed Buchwald–Hartwig amination for lenalidomide-derived aryl bromides was optimised using high throughput experimentation (HTE). The substrate scope of the optimised conditions was evaluated for a range of alkyl- and aryl- amines and functionalised aryl bromides. The methodology allows access to new cereblon-based bifunctional proteolysis targeting chimeras with a reduced step count and improved yields. 相似文献
4.
WANG Shihui LI Haiyan WANG Yue GAO Yang YU Shanshan ZHAO Qianqian JIN Xiangqun LU Haibin 《高等学校化学研究》2018,34(2):221-228
In this paper, we synthesized a series of proteolysis targeting chimeras(PROTACs) using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC50 value of (18.6±1.3) nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of (34.2±4.3) nmol/L and capable of inducing degradation of BRD4 protein at 0.4—0.6 µmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRD4 degrader. 相似文献
5.
Hanqiao Xu Dr. Takashi Kurohara Reina Takano Dr. Hidetomo Yokoo Dr. Norihito Shibata Dr. Nobumichi Ohoka Dr. Takao Inoue Prof. Mikihiko Naito Dr. Yosuke Demizu 《ChemistryOpen》2022,11(7):e202200131
Optimizing linker design is important for ensuring efficient degradation activity of proteolysis-targeting chimeras (PROTACs). Therefore, developing a straightforward synthetic approach that combines the protein-of-interest ligand (POI ligand) and the ligand for E3 ubiquitin ligase (E3 ligand) in various binding styles through a linker is essential for rapid PROTAC syntheses. Herein, a solid-phase approach for convenient PROTAC synthesis is presented. We designed azide intermediates with different linker lengths to which the E3 ligand, pomalidomide, is attached and performed facile PROTACs synthesis by forming triazole, amide, and urea bonds from the intermediates. 相似文献
6.
Jiajun Dong Jinmin Miao Yiming Miao Zihan Qu Sheng Zhang Peipei Zhu Florian Wiede Brenson A. Jassim Yunpeng Bai Quyen Nguyen Jianping Lin Lan Chen Tony Tiganis W. Andy Tao Zhong-Yin Zhang 《Angewandte Chemie (International ed. in English)》2023,62(22):e202303818
Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU-14 for both PTP1B and TC-PTP. DU-14 mediated PTP1B and TC-PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination- and proteasome-dependent. DU-14 enhances IFN-γ induced JAK1/2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. DU-14 also activates CD8+ T-cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU-14 induces PTP1B and TC-PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU-14, as the first PTP1B and TC-PTP dual degrader, merits further development for treating cancer and other indications. 相似文献
7.
Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned. 相似文献
8.
Xiao-Jing Pang Xiu-Juan Liu Yuan Liu Wen-Bo Liu Yin-Ru Li Guang-Xi Yu Xin-Yi Tian Yan-Bing Zhang Jian Song Cheng-Yun Jin Sai-Yang Zhang 《Molecules (Basel, Switzerland)》2021,26(14)
FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents. 相似文献
9.
10.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(38):11688-11691
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt), and removal of toxic mHtt is expected to be an effective therapeutic approach. We designed two small hybrid molecules ( 1 and 2 ) by linking a ligand for ubiquitin ligase (cellular inhibitor of apoptosis protein 1; cIAP1) with probes for mHtt aggregates, anticipating that these compounds would recruit cIAP1 to mHtt and induce selective degradation by the ubiquitin‐proteasome system. The synthesized compounds reduced mHtt levels in HD patient fibroblasts and appear to be promising candidates for the development of a treatment for HD. 相似文献