- From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase
-
Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analogue EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37). Here we present the synthesis of new inhibitors of Aurora B kinase, which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F"and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.
- Juillet, Charlotte,Ermolenko, Ludmila,Boyarskaya, Dina,Baratte, Blandine,Josselin, Béatrice,Nedev, Hristo,Bach, Stéphane,Iorga, Bogdan I.,Bignon, Jér?me,Ruchaud, Sandrine,Al-Mourabit, Ali
-
p. 1197 - 1219
(2021/02/05)
-
- COMPOUNDS AND THEIR METHODS OF USE
-
The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.
- -
-
Page/Page column 80; 81
(2018/06/12)
-
- IRAK-4 inhibitors. Part III: A series of imidazo[1,2-a]pyridines
-
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
- Buckley, George M.,Fosbeary, Richard,Fraser, Joanne L.,Gowers, Lewis,Higueruelo, Alicia P.,James, Lynwen A.,Jenkins, Kerry,Mack, Stephen R.,Morgan, Trevor,Parry, David M.,Pitt, William R.,Rausch, Oliver,Richard, Marianna D.,Sabin, Verity
-
scheme or table
p. 3656 - 3660
(2009/04/10)
-