- Development of anti-breast cancer PI3K inhibitors based on 7-azaindole derivatives through scaffold hopping: Design, synthesis and in vitro biological evaluation
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Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.
- Chen, Yi,Deng, Mingli,Jia, Yu,Ling, Yun,Liu, Xiaofeng,Lu, Mingzhu,Qiu, Tianze,Xiang, Ruiqing,Yang, Chengbin,Yang, Yongtai,Zhou, Yaming
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supporting information
(2021/10/19)
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- PI3 KINASE INHIBITORS AND USES THEREOF
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A compound of the formula (II); a pharmaceutical composition comprising same; and methods for treating a fibrotic disease in a subject.
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Paragraph 00190
(2021/10/15)
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- PI3K/mTOR protein degradation targeting chimeric compound as well as preparation method and medical application of PI3K/mTOR protein degradation targeting chimeric compound
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The invention relates to a PI3K/mTOR protein degradation targeting chimeric body (PROTAC) compound as well as a preparation method and medical application thereof. Specifically, the present inventionrelates to a compound represented by a general formula (
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Paragraph 0244; 0247; 0250-0251
(2021/02/10)
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- Imidazopyrazine derivative and synthesis method and application thereof
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The invention discloses 6-(6 substituent group-5-sulfonamido-3-pyridine) imidazo [1, 2-a] pyrazine derivatives as shown in a formula (I) or pharmaceutically acceptable salts thereof. The invention also discloses application of the 6-(6-substituent-5-sulfo
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Paragraph 0096-0104
(2020/12/29)
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- FIBROBLAST ACTIVATION PROTEIN (FAP) TARGETED IMAGING AND THERAPY IN FIBROSIS
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Excessive deposition of extracellular matrix is a hallmark of Idiopathic pulmonary fibrosis (IPF), it is advantageous to target the cells and the mechanisms associated with this process. By targeting myofibroblasts (specialized contractile fibroblasts) th
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Page/Page column 22
(2020/05/21)
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- Identification of novel thiazolo[5,4-b]pyridine derivatives as potent phosphoinositide 3-kinase inhibitors
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A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in mo
- Dong, Yi,Lin, Songwen,Tian, Hua,Xia, Liang,Xu, Heng,Zhang, Jingbo,Zhang, Kehui,Zhang, Yan
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- Design, synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors
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A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC50 values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K inhibitor and could be considered as a potential candidate for the development of anticancer agents.
- Ding, Huai-Wei,Wang, Shu,Qin, Xiao-Chun,Wang, Jian,Song, Hong-Rui,Zhao, Qing-Chun,Song, Shao-Jiang
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p. 2729 - 2740
(2019/05/17)
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- Aromatic heterocyclic compound serving as PI3K/mTOR kinase regulator and preparation method and application of aromatic heterocyclic compound
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The invention discloses 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-a]pyridines shown as a formula (I) or 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-b]pyridazine derivatives or pharmaceutically acceptable salts thereof and a preparation method. The invention also discloses application of 6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-a]pyridines or6-(6-substituted group-5-sulfonamido-3-pyridinyl)imidazo[1,2-b]pyridazine derivatives or pharmaceutically acceptable salts thereof to preparation of medicines for resisting tumors, treating cerebral ischemia and treating diabetes mellitus as a PI3K/mTOR inhibitor.
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Paragraph 0125; 0158; 0159; 0160; 0161
(2019/08/12)
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- Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents
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Phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, autophagy and apoptosis. Class I PI3K is frequently mutated and overexpressed in a lot of human cancers and PI3K was considered as a target for therapeutic treatment of cancer. In this study, we designed and synthesized a series of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives and evaluated their anticancer activity and the compound 8i was identified as a lead compound. Compound 8i with the most potent antiproliferative activity was selected for further biological mechanism. The PI3K kinase assay have shown potent efficiency against four subtypes of PI3K with an IC50 of 0.5–1.9 nM. Molecular docking showed a possible formation of H-bonding with essential amino acid residues. Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells.
- Ding, Huai-Wei,Yu, Lu,Bai, Meng-xuan,Qin, Xiao-Chun,Song, Man-tong,Zhao, Qing-Chun
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- Micro-reactor tandem synthesis method of indole anticancer drug molecules
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The invention relates to a micro-reactor tandem synthesis method of indole anticancer drug molecules. The method comprises the following steps: a reaction liquid 1 and a reaction liquid 2 are mixed, then are introduced into a first micro-reactor, and are reacted to obtain a first effluent, the first effluent and a reaction liquid 3 are mixed, then are introduced into a second micro-reactor, and are reacted to obtain a second effluent, the second effluent and a reaction liquid 4 are mixed, then are introduced into a third micro-reactor, and are reacted to obtain a final effluent, and the finaleffluent is concentrated and separated to obtain the indole anticancer drug molecules, wherein the reaction liquid 1 is a mixed solution containing 5-bromine-3-amino-2-substituted (R1)-pyridine, the reaction liquid 2 is substituted (R2)-benzenesulfonyl chloride, the reaction liquid 3 is a mixed solution containing bis(pinacolato)diboron, the reaction liquid 4 is a mixed solution containing a 5-bromo-7-azaindole derivative, and the indole anticancer drug molecules are benzenesulfonamidopyridylazaindole compounds. Compared with the prior art, the method of the invention has the advantages of high reaction efficiency, few side reactions and simple production process.
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Paragraph 0142-0144
(2019/12/08)
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- Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors
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A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-prolifer
- Lin, Songwen,Wang, Chunyang,Ji, Ming,Wu, Deyu,Lv, Yuanhao,Sheng, Li,Han, Fangbin,Dong, Yi,Zhang, Kehui,Yang, Yakun,Li, Yan,Chen, Xiaoguang,Xu, Heng
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supporting information
p. 637 - 646
(2018/01/05)
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- Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment
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Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.
- Lin, Songwen,Wang, Chunyang,Ji, Ming,Wu, Deyu,Lv, Yuanhao,Zhang, Kehui,Dong, Yi,Jin, Jing,Chen, Jiajing,Zhang, Jingbo,Sheng, Li,Li, Yan,Chen, Xiaoguang,Xu, Heng
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supporting information
p. 6087 - 6109
(2018/07/05)
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- Design, synthesis and biological evaluation of novel 4-aminoquinazolines as dual target inhibitors of EGFR-PI3Kα
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The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development
- Ding, Huai-Wei,Deng, Cheng-Long,Li, Dan-Dan,Liu, Dan-Dan,Chai, Shao-Meng,Wang, Wei,Zhang, Yan,Chen, Kai,Li, Xin,Wang, Jian,Song, Shao-Jiang,Song, Hong-Rui
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p. 460 - 470
(2018/02/14)
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- Novel 4-aminoquinazoline derivatives induce growth inhibition, cell cycle arrest and apoptosis via PI3Kα inhibition
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Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα β γ δ), the PIK3CA gene encoding PI3K
- Fan, Yan-Hua,Ding, Huai-Wei,Liu, Dan-Dan,Song, Hong-Rui,Xu, Yong-Nan,Wang, Jian
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p. 1675 - 1685
(2018/02/23)
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- Design, synthesis and biological evaluation of novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold derivatives as PI3Kα inhibitors
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The abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.
- Dong, Fu-Dan,Liu, Dan-Dan,Deng, Cheng-Long,Qin, Xiao-chun,Chen, Kai,Wang, Jian,Song, Hong-Rui,Ding, Huai-Wei
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p. 3982 - 3991
(2018/06/26)
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- Design, synthesis, and biological evaluation of novel 3-substituted imidazo[1,2-a]pyridine and quinazolin-4(3H)-one derivatives as PI3Kα inhibitors
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Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K
- Fan, Yan-Hua,Li, Wei,Liu, Dan-Dan,Bai, Meng-Xuan,Song, Hong-Rui,Xu, Yong-Nan,Lee, SangKook,Zhou, Zhi-Peng,Wang, Jian,Ding, Huai-Wei
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- Substituted arylsulphonamides as inhibitors of perforin-mediated lysis
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The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection.
- Spicer, Julie A.,Miller, Christian K.,O'Connor, Patrick D.,Jose, Jiney,Huttunen, Kristiina M.,Jaiswal, Jagdish K.,Denny, William A.,Akhlaghi, Hedieh,Browne, Kylie A.,Trapani, Joseph A.
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p. 139 - 155
(2017/06/07)
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- Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma
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The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is related to cellular activities. Abnormalities of this signaling pathway were discovered in various cancers, including hepatocellular carcinoma (HCC). The PI3K/mTOR dual inhibitors were proposed to have enhanced antitumor efficacies by targeting multiple points of the signaling pathway. We synthesized a series of propynyl-substituted benzenesulfonamide derivatives as PI3K/mTOR dual inhibitors. Compound 7k (NSC781406) was identified as a highly potent dual inhibitor, which exhibited potent tumor growth inhibition in the hepatocellular carcinoma BEL-7404 xenograft model. Compound 7k may be a potential therapeutic drug candidate for HCC.
- Chen, Ying,Zhang, Ling,Yang, Chao,Han, Jinsong,Wang, Chongqing,Zheng, Canhui,Zhou, Youjun,Lv, Jiaguo,Song, Yunlong,Zhu, Ju
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p. 957 - 966
(2016/02/19)
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- Indazole derivatives for use in the treatment of influenza virus infection
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The present invention is directed to compounds for use in the treatment or prevention of influenza virus infection.
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- PI3 kinase modulators and methods of use thereof, and use thereof
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The invention belongs to the field of medicines, concretely relates to a compound for treating cancer, a composition and an application of the composition and particularly relates to a PI3 kinase regulator as well as a use method and application of the PI3 kinase regulator. The invention provides a compound as shown in the formula (I), a pharmaceutically accepted salt of the compound and a pharmaceutical preparation of the compound, wherein the compound is used for regulating the activity of protein kinase and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the compound and a method for treating high-proliferative diseases of mammals and particularly human beings by using the pharmaceutical composition as shown in the formula (I).
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- Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor
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The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1.3, 1.8, 1.5, 3.8 and 3.8?nM for PI3Kα, β, γ, δ, and mTOR, respectively. 13b was further evaluated in NCI by an in?vitro cytotoxic screening program. Broad-spectrum antitumor activities with mean GI50value of 18.6?nM against approximately 60 human tumor cell lines were found. 13b displayed favorable physicochemical properties and superior pharmacokinetic profiles for animal studies. It significantly inhibited tumor growth when administered orally in an A549 non-small-cell lung carcinoma xenograft and BEL7404 human hepatocellular carcinoma xenograft models. On the basis of its excellent in?vivo efficacy and superior pharmacokinetic profiles, 13b has been selected for further preclinical investigation as a promising anticancer drug candidate.
- Han, Jinsong,Chen, Ying,Yang, Chao,Liu, Ting,Wang, Mingping,Xu, Haojie,Zhang, Ling,Zheng, Canhui,Song, Yunlong,Zhu, Ju
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p. 684 - 701
(2016/07/21)
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- Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors
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Abstract A novel series of 4-alkynyl-quinoline derivatives were designed, synthesized and biologically evaluated for their PI3Kα inhibitory activities and anti-proliferative effects against two cancer cell lines PC-3 and HCT-116. Most of them showed potent PI3Kα inhibitory activities with IC50 values at low nanomolar level and good to excellent anti-proliferative effects against both cell lines. Among them, compound 15d, the most potent one, was selected for further biological evaluation. As a result, 15d displayed strong inhibitory activity against other class I PI3K isoforms (PI3Kβ, PI3Kγ and PI3Kδ) and mTOR with an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that the phosphorylation of Akt, another downstream effector of PI3K, can be remarkably suppressed by 15d at cellular level. All these experimental results suggested that 15d is a potent PI3K/mTOR dual inhibitor and could serve as a promising lead compound for the development of anticancer agents.
- Lv, Xiaoqing,Ying, Huazhou,Ma, Xiaodong,Qiu, Ni,Wu, Peng,Yang, Bo,Hu, Yongzhou
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- PERFORIN INHIBITING BENZENESULFONAMIDE COMPOUNDS, PREPARATION AND USES THEREOF
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Compounds of formula (la) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, -C1-Cealkyl, -C1-Ceaminoalkyl, -C1-C6hydroxyalkyl, -haloC1-C6alkyl, -C1- C6alkoxyl, -haloC1-C6alkyl, -CH2OC(O)CrC6alkyl, -C(O)OC1,-C6alkyI, -NHC(O)C1,-C6alkyl, -NHS(O)2C1- C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NH2, and -C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from -NJJ, -OJ, halo,C1 -C6alkyl, -haloC1- C6alkyl, -C1-C6alkoxy, -haloC1-C6alkoxyl, and -C(0)NJJ; Ring C is is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, -S(0)2-NH-, -C(0)-NH-, -NH-C(0)-NH-, -S(0)2-NH-C(0)-NH-, -S(0)2-NH-C(0) - and -CH=CH-; wherein Rings B and C, and Rings C and D, are connected to each other via a C-C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C1-C6alkyl or optionally substituted haloC1-C6alkyl.
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Page/Page column 87; 90
(2014/03/25)
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- PI3 KINASE MODULATORS AND METHODS OF USE
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This invention relates to the field of lipid kinases and modulators thereof. In particular, the invention relates to modulators of phosphatidylinositol 3-kinases (PI3 kinases or PBKs) signaling pathways, and methods of their use. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in modulating of PI3K signaling pathways and their related disorders in mammals, especially humans.
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- HETEROAROMATIC COMPOUNDS AS PI3 KINASE MODULATORS AND METHODS OF USE
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The present invention provides heteroaromatic derivatives and pharmaceutical acceptable salts and formulations thereof useful in modulating the protein kinase activity, especially phosphatidylinositol 3-kinases (PI3 kinases) and mTOR, and in modulating inter- and/or intra-cellular signaling activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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- Discovery of selective small molecule type III phosphatidylinositol 4-kinase alpha (PI4KIIIα) inhibitors as anti hepatitis C (HCV) agents
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Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIIIα is an essential component of these replication organelles. RNA interference of PI4KIIIα results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIIIα is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients.1 We investigated if small molecule inhibitors of PI4KIIIα could inhibit HCV replication in vitro. The synthesis and structure-activity relationships associated with the biological inhibition of PI4KIIIα and HCV replication are described. These efforts led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIIIα and potently inhibits HCV replication in vitro.
- Leivers, Anna L.,Tallant, Matthew,Shotwell, J. Brad,Dickerson, Scott,Leivers, Martin R.,McDonald, Octerloney B.,Gobel, Jeff,Creech, Katrina L.,Strum, Susan L.,Mathis, Amanda,Rogers, Sabrinia,Moore, Chris B.,Botyanszki, Janos
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p. 2091 - 2106
(2014/04/03)
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- 5-Alkynyl-pyridines
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This invention relates to 5-alkynyl-pyridine of general formula (I) their use as inhibitors of the activity of PI3Kalpha, pharmaceutical compositions containing them, and their use as a medicaments for the treatment and/or prevention of diseases characterized by excessive or abnormal cell proliferation and associated conditions such as cancer. The groups R1 to R6 and n have the meanings given in the claims and in the specification
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- NEW 5-ALKYNYL-PYRIDINES
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5-alkynyl-pyridine of general formula (I) which are inhibitors of the activity of PI3K alpha, and their use in the treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer.
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- Synthesis and anticancer activity evaluation of a series of [1,2,4] triazolo[1,5-a]pyridinylpyridines in vitro and in vivo
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A series of [1,2,4]triazolo[1,5-a]pyridinylpyridines were synthesized and characterized. Their anti-proliferative activities in vitro were evaluated by MTT against three human cancer cell lines including HCT-116, U-87 MG and MCF-7 cell lines. The SAR of target compounds was preliminarily discussed. The compounds 1c and 2d with potent antiproliferative activities were tested for their effects on the AKT and p-AKT473. The anticancer effect of 1c was evaluated in mice bearing sarcoma S-180 model. The results suggest that the title compounds are potent anticancer agents.
- Wang, Xiao-Meng,Xu, Jing,Li, Yi-Ping,Li, Huan,Jiang, Cong-Shan,Yang, Guang-De,Lu, She-Min,Zhang, San-Qi
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p. 243 - 251
(2013/10/01)
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- METHOD OF ADMINISTRATION AND TREATMENT
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The present invention provides a method of treating a human with cancer comprising detecting at least one mutation in a PIK3CA gene or at least one mutant protein encoded by said PIK3CA gene from at least one first sample from said human and administering to said human an effective amount of 2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide or a pharmaceutically acceptable salt thereof in a pharmaceutical composition if said at least one sample has at least one mutant PI3K protein or a mutation in the PIK3CA gene.
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- [11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers
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GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [11C]GSK2126458 and [18F]GSK212 6458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40-50% and 20-30% decay corrected radiochemical yield, and 370-740 and 37-222 GBq/lmol specific activity at end of bombardment (EOB), respectively.
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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p. 1569 - 1574
(2012/04/04)
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- NEW 5-ALKYNYL-PYRIDINES
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This invention relates to 5-alkynyl-pyridine of general formula (I) their use as inhibitors of the activity of PI3Kalpha, pharmaceutical compositions containing them, and their use as a medicaments for the treatment and/or prevention of diseases characterized by excessive or abnormal cell proliferation and associated conditions such as cancer. The groups R1 to R6 and n have the meanings given in the claims and in the specification.
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- NEW 5-ALKYNYL-PYRIDINES
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This invention relates to 5-alkynyl-pyridine of general formula (I) their use as inhibitors of the activity of P13Kalpha, pharmaceutical compositions containing them, and their use as a medicaments for the treatment and/or prevention of diseases characterized by excessive or abnormal cell proliferation and associated conditions such as cancer. The groups R1 to R6 and n have the meanings given in the claims and in the specification.
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- BENZIMIDAZOLE DERIVATIVES AS ANTIVIRAL AGENTS
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Provided are compounds of Formulas I, II, III, IV, V, and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).
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- 4-OXADIAZOL-2 -YL- INDAZOLES AS INHIBITORS OF P13 KINASES
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3-kinase activity.
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Page/Page column 101; 102
(2010/10/03)
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- PYRIDOPYRIMIDINE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PB kinases using pyridoprimidine derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of pyridopyrimidine derivatives.
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Page/Page column 54
(2009/04/25)
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- PYRIDOSULFONAMIDE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of PB kinases using pyridosulfonamide derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of pyridosulfonamide derivatives.
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Page/Page column 86
(2009/05/30)
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- 4-CARBOXAMIDE INDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF P13-KINASES
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of P13-kinase activity.
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Page/Page column 117-118
(2009/12/28)
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- QUINAZOLINE DERIVATIVES AS PI3 KINASE INHIBITORS
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Invented is a method of inhibiting the activity/function of P13 kinases using quinazoline derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of quinazoline derivatives.
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