- Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)
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PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC50 values: ~10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.
- Kaniskan, H. ümit,Eram, Mohammad S.,Zhao, Kehao,Szewczyk, Magdalena M.,Yang, Xiaobao,Schmidt, Keith,Luo, Xiao,Xiao, Sean,Dai, Miao,He, Feng,Zang, Irene,Lin, Ying,Li, Fengling,Dobrovetsky, Elena,Smil, David,Min, Sun-Joon,Lin-Jones, Jennifer,Schapira, Matthieu,Atadja, Peter,Li, En,Barsyte-Lovejoy, Dalia,Arrowsmith, Cheryl H.,Brown, Peter J.,Liu, Feng,Yu, Zhengtian,Vedadi, Masoud,Jin, Jian
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p. 1204 - 1217
(2018/02/17)
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- SERINE/THREONINE KINASE INHIBITORS
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Compounds having the formula I wherein R2, X and Z as defined herein are inhibitors of ERK kinase. Also disclosed are compositions and methods for treating hyperproliferative disorders.
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Paragraph 0349-0350
(2014/03/25)
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- FLUOROISOQUINOLINE SUBSTITUTED THIAZOLE COMPOUNDS AND METHODS OF USE
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The invention relates to thiazole compounds of Formula (I) and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the therapeutic use of such thiazole compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 54; 55-56
(2010/08/08)
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- THIADIAZOLE MODULATORS OF PKB
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The invention relates to thiazole compounds of Formula I and Formula II and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the th
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Page/Page column 188; 189-190
(2009/03/07)
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- HETEROCYCLIC MODULATORS OF PKB
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The invention relates to heterocyclic compounds of Formula I and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein Formula (I). The invention also relates to the therapeutic use of such compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 159-160
(2009/03/07)
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- Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity
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The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t1/2 = 0.3 h, po F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t1/2 = 5.0 h, po F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.
- Zhu, Gui-Dong,Gong, Jianchun,Claiborne, Akiyo,Woods, Keith W.,Gandhi, Viraj B.,Thomas, Sheela,Luo, Yan,Liu, Xuesong,Shi, Yan,Guan, Ran,Magnone, Shayna R.,Klinghofer, Vered,Johnson, Eric F.,Bouska, Jennifer,Shoemaker, Alexander,Oleksijew, Anatol,Stoll, Vincent S.,Jong, Ron De,Oltersdorf, Tilman,Li, Qun,Rosenberg, Saul H.,Giranda, Vincent L.
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p. 3150 - 3155
(2007/10/03)
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