- KINASE ANTAGONISTS AND METHODS FOR MAKING AND USING THEM
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Disclosed herein are small molecule compounds that are SGK1 antagonists, formulations and pharmaceutical compositions comprising the compounds, and methods of making and using them, for treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme of the AGC group of kinases including SGK1, by administration of an AGC kinase inhibitor or antagonist.
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Page/Page column 95-96
(2020/02/19)
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- Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
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Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 μM, 0.064 μM, 0.16 μM and 0.49 μM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.
- Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
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p. 2801 - 2812
(2019/05/15)
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- NAPHTHYRIDINES AS INHIBITORS OF HPK1
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Naphthyridine compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the naphthyridine compounds.
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Paragraph 2033; 2034
(2018/10/21)
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- Novel ATP-competitive kinesin spindle protein inhibitors
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Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D 130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.
- Parrish, Cynthia A.,Adams, Nicholas D.,Auger, Kurt R.,Burgess, Joelle L.,Carson, Jeffrey D.,Chaudhari, Amita M.,Copeland, Robert A.,Diamond, Melody A.,Donatelli, Carla A.,Duffy, Kevin J.,Faucette, Leo F.,Finer, Jeffrey T.,Huffman, William F.,Hugger, Erin D.,Jackson, Jeffrey R.,Knight, Steven D.,Luo, Lusong,Moore, Michael L.,Newlander, Ken A.,Ridgers, Lance H.,Sakowicz, Roman,Shaw, Antony N.,Sung, Chiu-Mei M.,Sutton, David,Wood, Kenneth W.,Zhang, Shu-Yun,Zimmerman, Michael N.,Dhanak, Dashyant
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p. 4939 - 4952
(2008/03/11)
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- A mild, convenient synthesis of sulfinic acid salts and sulfonamides from alkyl and aryl halides
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A general, mild, and convenient method has been developed for the synthesis of various alkyl and aryl sulfinic acid salts and sulfonamides from the corresponding halides. Key to the success of this methodology is the design and facile synthesis of sodium 3-methoxy-3-oxopropane-1-sulfinate (SMOPS), a reagent that serves to introduce the protected sulfinate moiety directly to the substrate, thus avoiding the use of oxidizing and other harsh reaction conditions such as organolithium or Grignard reagents. Many functional groups, as well as heterocycles, are tolerated in the sequence.
- Baskin, Jeremy M,Wang, Zhaoyin
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p. 8479 - 8483
(2007/10/03)
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