- 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones designed by a “cut and glue” strategy are dual aurora a/vegf-r kinase inhibitors
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Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.
- Berger, Bianca,Chaikuad, Apirat,Karatas, Mehmet,Knapp, Stefan,Kubbutat, Michael H. G.,Kunick, Conrad,Totzke, Frank
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supporting information
(2021/06/16)
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- Fragment based search for small molecule inhibitors of HIV-1 Tat-TAR
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Basic molecular building blocks such as benzene rings, amidines, guanidines, and amino groups have been combined in a systematic way to generate ligand candidates for HIV-1 TAR RNA. Ranking of the resulting compounds was achieved in a fluorimetric Tat-TAR
- Zeiger, Mirco,Stark, Sebastian,Kalden, Elisabeth,Ackermann, Bettina,Ferner, Jan,Scheffer, Ute,Shoja-Bazargani, Fatemeh,Erdel, Veysel,Schwalbe, Harald,G?bel, Michael W.
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supporting information
p. 5576 - 5580
(2015/01/08)
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- Crystal structure of liganded cFMS kinase domain
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A crystal structure of the cfms kinase domain, co-crystal structure with a bound small molecule, as well as methods of using the same in the discovery of cfms inhibitors and in the treatment of diseases mediated by inappropriate cfms activity.
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Page/Page column 21
(2008/06/13)
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- Pyrazolopyridine antiherpetics: SAR of C2′ and C7 amine substituents
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A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage interm
- Johns, Brian A.,Gudmundsson, Kristjan S.,Turner, Elizabeth M.,Allen, Scott H.,Samano, Vicente A.,Ray, John A.,Freeman, George A.,Boyd Jr., F. Leslie,Sexton, Connie J.,Selleseth, Dean W.,Creech, Katrina L.,Moniri, Kelly R.
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p. 2397 - 2411
(2007/10/03)
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- A novel series of potent and selective IKK2 inhibitors
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A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling.
- Bingham, Alistair H.,Davenport, Richard J.,Gowers, Lewis,Knight, Roland L.,Lowe, Christopher,Owen, David A.,Parry, David M.,Pitt, Will R.
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p. 409 - 412
(2007/10/03)
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- 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity
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Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM Kis against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.
- Wang, Shudong,Meades, Christopher,Wood, Gavin,Osnowski, Andrew,Anderson, Sian,Yuill, Rhoda,Thomas, Mark,Mezna, Mokdad,Jackson, Wayne,Midgley, Carol,Griffiths, Gary,Fleming, Ian,Green, Simon,McNae, Iain,Wu, Su-Ying,McInnes, Campbell,Zheleva, Daniella,Walkinshaw, Malcolm D.,Fischer, Peter M.
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p. 1662 - 1675
(2007/10/03)
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- N-phenyl-4-pyrazolo[1,5-6]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy
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Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b] pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.
- Tavares, Francis X.,Boucheron, Joyce A.,Dickerson, Scott H.,Griffin, Robert J.,Preugschat, Frank,Thomso, Stephen A.,Wang, Tony Y.,Zhouf, Hui-Qiang
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p. 4716 - 4730
(2007/10/03)
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- PYRADAZINE COMPOUNDS AS GSK-3 INHIBITORS
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The present invention relates generally to inhibitors of the kinases, such as GSK3, and more particularly to fused pyradazine compounds according to formula (I) and methods of their use.
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