- Synthesis and biological evaluation of (: E)-4-(3-arylvinyl-1 H -indazol-6-yl)pyrimidin-2-amine derivatives as PLK4 inhibitors for the treatment of breast cancer
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Polo-like kinase 4 (PLK4), a vital regulator of centriole duplication, is important for maintaining genome stability. Dysregulation of PLK4 has been found in several human cancers and is associated with a predisposition to tumorigenesis. Herein, we describe the discovery of (E)-4-(3-arylvinyl-1H-indazol-6-yl)pyrimidin-2-amine derivatives as potent PLK4 inhibitors with more concise structure using a scaffold hopping strategy. SAR exploration and preliminary assessment identified 14i as a new PLK4 inhibitor which displayed excellent potency in vitro. 14i could inhibit the activity of PLK4, perturb centriole replication, result in mitosis disorder and induce cell apoptosis in breast cancer cells. Moreover 14i demonstrated significant antitumor efficacy in the MDA-MB-468 and MDA-MB-231 xenograft models. This study suggested that this concise chemotype would represent a promising scaffold of PLK4 inhibitors for cancer therapy and 14i would be an attractive lead compound for further optimization and evaluation.
- Liu, Zhihao,Lei, Qian,Wei, Wei,Xiong, Lu,Shi, Yaojie,Yan, Guoyi,Gao, Chao,Ye, Tinghong,Wang, Ningyu,Yu, Luoting
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Read Online
- ALPHA-5 BETA-1 INHIBITORS
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The disclosure provides, inter alia, alpha-5 beta-1 inhibitors, pharmaceutical compositions comprising alpha-5 beta-1 inhibitors, methods for treating diseases using alpha-5 beta-1 inhibitors, and processes for making alpha-5 beta-1 inhibitors.
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Paragraph 0759; 0902-0905
(2021/06/11)
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- Compound with AMPK agonistic activity and preparation and application of prodrug thereof
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The invention relates to a compound with AMPK agonistic activity and a prodrug thereof, and as well as a preparation method and medical application of a prodrug thereof. The compound has the structure shown in the formula (I), and the prodrug of the compound has the structure shown in the formula (II), wherein each group and the substituent are as defined in the specification. The invention discloses a preparation method of the compound and application of the compound in prevention and treatment AMPK related diseases, and the AMPK related diseases include, but are not limited to, energy metabolism abnormality related diseases. Neurodegenerative diseases and inflammation-related diseases and the like.
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Paragraph 0145; 0149-0150; 0359; 0363-0364
(2021/10/27)
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- Hit-to-Lead Optimization of Benzoxazepinoindazoles As Human African Trypanosomiasis Therapeutics
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Human African trypanosomiasis (HAT) is a neglected tropical disease caused by infection with either of two subspecies of the parasite Trypanosoma brucei. Due to a lack of economic incentive to develop new drugs, current treatments have severe limitations in terms of safety, efficacy, and ease of administration. In an effort to develop new HAT therapeutics, we report the structure-activity relationships around T. brucei for a series of benzoxazepinoindazoles previously identified through a high-throughput screen of human kinase inhibitors, and the subsequent in vivo experiments for HAT. We identified compound 18, which showed an improved kinase selectivity profile and acceptable pharmacokinetic parameters, as a promising lead. Although treatment with 18 cured 60% of mice in a systemic model of HAT, the compound was unable to clear parasitemia in a CNS model of the disease. We also report the results of cross-screening these compounds against T. cruzi, L. donovani, and S. mansoni.
- Klug, Dana M.,Tschiegg, Laura,Diaz, Rosario,Rojas-Barros, Domingo,Perez-Moreno, Guiomar,Ceballos, Gloria,García-Hernández, Raquel,Martinez-Martinez, Maria Santos,Manzano, Pilar,Ruiz, Luis Miguel,Caffrey, Conor R.,Gamarro, Francisco,Pacanowska, Dolores Gonzalez,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
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p. 2527 - 2546
(2019/11/28)
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- HETEROCYCLIC COMPOUND AS SYK INHIBITOR AND/OR SYK-HDAC DUAL INHIBITOR
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A heterocyclic compound as a Syk inhibitor and/or a Syk-HDAC dual inhibitor, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, and solvates thereof. Specifically, the present invention relates to a compound of formula (I), the compound having dual inhibitory activity for Syk and/or Syk-HDAC.
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Paragraph 0118-0119
(2019/10/29)
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- PYRIDONE DERIVATIVES AND THEIR USE AS KINASE INHIBITORS
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Disclosed in the present application is a compound of formula (I) as defined herein as well as a pharmaceutical composition comprising said compound. Further disclosed in the present application is the use of such pharmaceutical compositions for treating diseases, namely inter alia for use in the treatment of cancer, metabolic, inflammatory, autoimmune and viral diseases. The compounds disclosed herein are inhibitors of MNK1 and/or MNK2 kinases.
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Page/Page column 182
(2017/05/10)
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- Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability
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Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.
- Wang, Xiaojing,Kolesnikov, Aleksandr,Tay, Suzanne,Chan, Grace,Chao, Qi,Do, Steven,Drummond, Jason,Ebens, Allen J.,Liu, Ning,Ly, Justin,Harstad, Eric,Hu, Huiyong,Moffat, John,Munugalavadla, Veerendra,Murray, Jeremy,Slaga, Dionysos,Tsui, Vickie,Volgraf, Matthew,Wallweber, Heidi,Chang, Jae H.
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p. 4458 - 4473
(2017/06/05)
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- HETEROARYL SUBSTITUTED PYRROLOTRIAZINE AMINE COMPOUNDS AS PI3K INHIBITORS
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Disclosed are compounds of Formula (I); or a salt thereof; wherein Qi is (i) C1, Br, I, -CN, -CH3, or -CF3; or (ii) pyrazole, triazole, or pyridinyl, each substituted with R1; Q2 is pyridinyl, indazolyl, isoquinolinyl, or benzo[d]imidazolyl substituted with R2 and R3; and R1, R2, and R3 are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.
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Page/Page column 75
(2016/06/06)
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- HEPARAN SULFATE BIOSYNTHESIS INHIBITORS FOR THE TREATMENT OF DISEASES
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Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions in need of inhibition of heparan sulfate biosynthesis.
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Paragraph 000170; 000184; 000194
(2016/05/02)
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- NOVEL 3-INDOL SUBSTITUTED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE
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The present invention relates to compound of Formula (I) or pharmaceutically acceptable enantiomers, salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as TDO2 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or HIV, depression, and obesity. The invention also relates to a process for manufacturing compounds of Formula (I).
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Page/Page column 87; 88
(2016/01/12)
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- ORGANIC COMPOUNDS AND ORGANIC ELECTRO LUMINESCENCE DEVICE COMPRISING THE SAME
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The present invention relates to organic compounds and an organic electroluminescent device comprising the same. According to the present invention, the organic compounds can improve light emitting efficiency, driving voltage, lifespan, etc. of the organic electroluminescent device by being used in an organic layer, desirably a light emitting layer of the organic electroluminescent device. The compounds are represented by chemical formula 1.COPYRIGHT KIPO 2015
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Paragraph 0282; 0283; 0284; 0299-0301
(2016/10/08)
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- NEW ORGANIC COMPOUNDS AND ORGANIC ELECTRO LUMINESCENCE DEVICE COMPRISING THE SAME
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The present invention refers to a fullerene derivative is denoted by chemical formula 1 a and is provided to improve quality of an organic electroluminescent including, a fullerene derivative is denoted by chemical formula 1 a at least one organic layer, preferably light-emitting layer by the inclusion of, the P-type semiconductor layer, , driving voltage, can be enhanced life: [Formula 1] (Said formula 1 in, R 1 to R 5 and Ar 1 each that are defined in the detailed description as).
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Paragraph 0120-0121; 0140-0142
(2016/10/09)
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- PROTEIN KINASE INHIBITORS
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Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating diseases using the compounds are disclosed.
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Page/Page column 50
(2010/11/28)
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