- Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: Exploration of diverse hinge-binding fragments
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Abstract VEGFR-2 plays an essential role in angiogenesis and is an important target for cancer therapy. A series of biphenyl-aryl ureas were synthesized and evaluated as novel VEGFR-2 inhibitors. The pyridine, methylamine carbonyl pyridine and pivaloyl amide pyridine were introduced as novel hinge binding fragment. The majority of title compounds displayed potent VEGFR-2 inhibition. In particular, L1, L9, W14 and W15 exhibited significant enzymatic inhibitory activity with IC50 values of 0.36 nM, 0.22 nM, 0.15 nM and 0.14 nM. Compounds L1, L9 and W15 displayed potent antiproliferative activity against A549 and SMMC-7721 cells. SAR study suggested that incorporation of 3-trifluoromethyl and methylamine carbonyl on terminal pyridine could improve VEGFR-2 inhibitory activity. Molecular docking illustrated that urea moiety formed two critical hydrogen bonds with the DFG residues of VEGFR-2. The results indicated that these biphenyl-aryl ureas could serve as promising lead compounds for further optimization.
- Su, Ping,Wang, Jinfeng,Shi, Yaling,Pan, Xiaoyan,Shao, Ruili,Zhang, Jie
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- NOVEL CONFORMATIONALLY-RESTRICTED ANALOGUES OF SORAFENIB AND REGORAFENIB AS SELECTIVE KINASE INHIBITORS FOR CANCER TREATMENT
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Novel conformationally-restricted analogues of sorafenib and regorafenib as selective kinase inhibitors for therapeutic formulations and methods for treating cancer.
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Paragraph 0074
(2022/02/11)
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- Design, synthesis, biological evaluation, and modeling studies of novel conformationally-restricted analogues of sorafenib as selective kinase-inhibitory antiproliferative agents against hepatocellular carcinoma cells
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Sorafenib is one of the clinically used anticancer agents that inhibits several kinases. In this study, novel indole-based rigid analogues of sorafenib were designed and synthesized in order to enhance kinase selectivity and hence minimize the side effect
- Sbenati, Rawan M.,Zaraei, Seyed-Omar,El-Gamal, Mohammed I.,Anbar, Hanan S.,Tarazi, Hamadeh,Zoghbor, Malaka M.,Mohamood, Najma A.,Khakpour, Mahta M.,Zaher, Dana M.,Omar, Hany A.,Alach, Nour N.,Shehata, Mahmoud K.,El-Gamal, Randa
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- Exploring the potential intracellular targets of vascular normalization based on active candidates
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We previously developed two candidates with potency of inducing vascular normalization, BD7 and B14. However, the definite intracellular molecular target(s) responsible for their activity remains unknown. Herein, we report the discovery and functional assessment of several multifunctional photoaffinity probes for determining the potential biological targets of active compounds. The probes bear a photoaffinity moiety and a bioorthogonal unit attached to B7 or B14 and maintained the bioactivity of the parent active molecules. Using in vitro biological assays, we preliminarily identified VEGFR-2 as a potential intracellular target for the active candidates. Our results demonstrate the utility of these multifunctional photoaffinity probes for analyzing the biological activity and subcellular localization of the intracellular target proteins of active candidates.
- Shan, Yuanyuan,Wang, Jin,Si, Ru,Ma, Yuexiang,Li, Jing,Zhang, Qingqing,Lu, Wen,Zhang, Jie
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supporting information
(2020/12/29)
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- SPIROCYCLIC COMPOUNDS
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Disclosed herein are spirocyclic compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
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- 8-ETHYL-6-(ARYL)PYRIDO [2,3-D]PYRIMIDIN-7(8H) -ONES FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS AND CANCER
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Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders or neurofibromatosis. Also described herein are methods of utilizing PAK inhibitors for the treatment of cancer.
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Paragraph 00562
(2013/04/10)
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