TY - JOUR
T1 - Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold.
AU - Niculescu-Duvaz, I
AU - Roman, E
AU - Whittaker, SR
AU - Friedlos, F
AU - Kirk, R
AU - Scanlon, IJ
AU - Davies, LC
AU - Niculescu-Duvaz, D
AU - Marais, R
AU - Springer, CJ
PY - 2008/6
Y1 - 2008/6
N2 - 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 (IC 50 = 3.5 microM) 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 50s 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.
AB - 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 (IC 50 = 3.5 microM) 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 50s 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.
UR - http://europepmc.org/abstract/med/18473434
U2 - 10.1021/jm070776b
DO - 10.1021/jm070776b
M3 - Article
C2 - 18473434
SN - 0022-2623
SP - 3261
EP - 3274
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -
