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Literature DB >> 16730979

Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.

Kyoung Soon Kim¹, Songfeng Lu, Lyndon A Cornelius, Louis J Lombardo, Robert M Borzilleri, Gretchen M Schroeder, Christopher Sheng, George Rovnyak, Donald Crews, Robert J Schmidt, David K Williams, Rajeev S Bhide, Sarah C Traeger, Patricia A McDonnell, Luciano Mueller, Steven Sheriff, John A Newitt, Andrew T Pudzianowski, Zheng Yang, Robert Wild, Frances Y Lee, Roberta Batorsky, James S Ryder, Marie Ortega-Nanos, Henry Shen, Marco Gottardis, Deborah L Roussell.

Abstract

Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.

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Year: 2006 PMID： 16730979 DOI： 10.1016/j.bmcl.2006.05.037

Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823

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Cited

13 in total

1. Dimeric Eg5 maintains processivity through alternating-site catalysis with rate-limiting ATP hydrolysis.

Authors: Troy C Krzysiak; Susan P Gilbert
Journal: J Biol Chem Date: 2006-10-23 Impact factor: 5.157

2. Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly.

Authors: Cheng Jiang; Yadong Chen; Xiaojian Wang; Qidong You
Journal: J Mol Model Date: 2007-06-23 Impact factor: 1.810

3. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site.

Authors: Ksenia Oguievetskaia; Laetitia Martin-Chanas; Artem Vorotyntsev; Olivia Doppelt-Azeroual; Xavier Brotel; Stewart A Adcock; Alexandre G de Brevern; Francois Delfaud; Fabrice Moriaud
Journal: J Comput Aided Mol Des Date: 2009-06-17 Impact factor: 3.686

Review 4. Kinesins and cancer.

Authors: Oliver Rath; Frank Kozielski
Journal: Nat Rev Cancer Date: 2012-07-24 Impact factor: 60.716

Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.

1. Dimeric Eg5 maintains processivity through alternating-site catalysis with rate-limiting ATP hydrolysis.

2. Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly.

3. Computational fragment-based drug design to explore the hydrophobic sub-pocket of the mitotic kinesin Eg5 allosteric binding site.

Review 4. Kinesins and cancer.

5. Discovery of Novel Allosteric Eg5 Inhibitors Through Structure-Based Virtual Screening.

6. The conserved L5 loop establishes the pre-powerstroke conformation of the Kinesin-5 motor, eg5.

7. NSC 622124 inhibits human Eg5 and other kinesins via interaction with the conserved microtubule-binding site.

8. Structure-activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors.

9. The structure of the ternary Eg5-ADP-ispinesib complex.

10. Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules.