Niculescu-Duvaz, I., Roman, E., Whittaker, S. R., Friedlos, F., Kirk, R., Scanlon, I. J., Davies, L. C., Niculescu-Duvaz, D., Marais, R., Springer, C. J. (2008) Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY, 51 (11). pp. 3261-3274. ISSN 0022-2623

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Abstract

BRAF, a serine/threonine kinase, plays a key role in the development of certain types of cancer, particularly melanoma. 2-(3,4,5-Trimethoxyphenylamino)-6-(3-acetamidophenyl)-pyrazine, 1, was identified as a low micromolar (IC50 = 3.5 mu M) BRAF inhibitor from a high-throughput screen of a library of 23000 compounds. This compound was chosen as the starting point of a program aimed at developing inhibitors of mutant (V600E)BRAF. We have already reported on the optimization of the trimethoxyphenylamino moiety of 1. In this paper, we describe the synthesis of a series of compounds derived from 1 with the purpose of optimization of the pyrazine central core and the phenylacetamido moiety in order to increase the potency against (V600E)BRAF compared to CRAF. The biological activity of the new inhibitors was assessed against mutant (V600E)BRAF in vitro. Several compounds were identified with IC(50)s of 300-500 nM for (V600E)BRAF, and all compounds that were assessed showed selectivity for (V600E)BRAF compared to CRAF by 5 -> 86-fold.

Item Type:	Article
Authors (ICR Faculty only):	Springer, Caroline and Marais, Richard and Niculescu-Duvaz, Ion and Niculescu-Duvaz, Dan
All Authors:	Niculescu-Duvaz, I., Roman, E., Whittaker, S. R., Friedlos, F., Kirk, R., Scanlon, I. J., Davies, L. C., Niculescu-Duvaz, D., Marais, R., Springer, C. J.
Uncontrolled Keywords:	KINASE INHIBITORS; ARYL CHLORIDES; ACTIVATION; MUTATIONS; AMINATION; PATHWAY; DESIGN; POTENT
Research teams:	Closed research groups > Signal Transduction ICR divisions > Cancer Therapeutics > Gene & Oncogene Targeting
Depositing User:	Users 10 not found.
Date Deposited:	14 Jul 2008 08:42
Last Modified:	08 Nov 2012 16:32
URI:	http://publications.icr.ac.uk/id/eprint/6558

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