- Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors
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BTK is an effective target for the treatment of B-cell malignant tumors and autoimmune diseases. In this work, a series of 2-phenyl pyrimidine derivatives were prepared and their preliminary in vitro activities on B-cell leukemia cells as well as the BTK enzyme were determined. The results showed that compound 11g displayed the best inhibitory activity on BTK with an inhibition rate of 82.76% at 100 nM and excellent anti-proliferation activity on three B-cell leukemia lines (IC50 = 3.66 μM, 6.98 μM, and 5.39 μM against HL60, Raji and Ramos, respectively). Besides, the flow cytometry analysis results indicated that 11g inhibited the proliferation of the Raji cells in a dose- and time-dependent manner, and blocked the Ramos cells at the G0/G1 phase, which is in accordance with the positive control ibrutinib. The mechanism investigation demonstrated that 11g could inhibit the phosphorylation of BTK and its downstream substrate phospholipase γ2 (PLCγ2). All these results showed that 11g was a promising lead compound that merited further optimization as a novel class of BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
- Li, Xinyu,Shi, Binyu,Teng, Yu,Cheng, Yu,Yang, Huizhu,Li, Jiurong,Wang, Lianjian,He, Siying,You, Qidong,Xiang, Hua
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p. 294 - 299
(2019/03/02)
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- 2-phenylpyrimidine compounds, preparation method and medical application
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The invention belongs to the field of medicines and particularly relates to 2-phenylpyrimidine compounds and pharmacologically-acceptable salts thereof and an isotope marker. The invention also discloses a pharmaceutical composition containing the substances and application of the pharmaceutical composition for treating diseases related with protein kinase activity, such as cancer and inflammation. (The formula is shown in the description).
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Paragraph 0098; 0099; 0124; 0125; 0126
(2018/06/15)
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- Identification of new pyrrolo[2,3-d]pyrimidines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, biological evaluation and molecular modeling
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Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC50 values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent.
- Adel, Mai,Serya, Rabah A.T.,Lasheen, Deena S.,Abouzid, Khaled A.M.
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p. 612 - 629
(2018/09/29)
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- PARP (poly (ADP-ribose) polymerase)-1 and Tankyrase1/2 multi-target inhibitors as well as preparation method and application thereof
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The invention relates to the field of medicinal chemistry, in particular to PARP (poly (ADP-ribose) polymerase)-1 and Tankyrase1/2 multi-target inhibitors containing a 1(2H)-phthalazinone structure and shown as formula (I) in the description, a preparatio
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Paragraph 0044; 0048
(2018/09/08)
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- Identification of Multiple Structurally Distinct, Nonpeptidic Small Molecule Inhibitors of Protein Arginine Deiminase 3 Using a Substrate-Based Fragment Method
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The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min-1 M-1 kinact/KI values and ≥10-fold selectivity for PAD3 over PADs 1, 2, and 4. (Figure Presented).
- Jamali, Haya,Khan, Hasan A.,Stringer, Joseph R.,Chowdhury, Somenath,Ellman, Jonathan A.
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p. 3616 - 3621
(2015/03/30)
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- Virtual screening and synthesis of new chemical scaffolds as VEGFR-2 kinase inhibitors
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Background: VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 k
- Elsayed,El-Araby,Serya,Abouzid
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p. 554 - 560
(2013/02/23)
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