Novel inhibitors of the v-raf murine sarcoma viral oncogene homologue B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold

被引：35

作者：

Niculescu-Duvaz, Ion ^{[1
]}

Roman, Esteban ^{[1
]}

Whittaker, Steven R.

Friedlos, Frank ^{[1
]}

Kirk, Ruth

Scanlon, Ian J. ^{[1
]}

Davies, Lawrence C. ^{[1
]}

Niculescu-Duvaz, Dan ^{[1
]}

Marais, Richard

Springer, Caroline J. ^{[1
]}

机构：

[1] Inst Canc Res, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 11期

基金：

英国惠康基金;

关键词：

D O I：

10.1021/jm070776b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3261 / 3274

页数：14

共 24 条

[1] Kinase inhibition with BAY 43-9006 n renal cell carcinoma [J].

Ahmad, T ;

Eisen, T .

CLINICAL CANCER RESEARCH, 2004, 10 (18) :6388S-6392S

[2]

BATT DB, 2004, USE ISOQUINOLINE DER, P85

[3]

BOLLAG G, 2004, CURR OPIN INVEST DR, V4, P1436

[4]

Chiloeches Antonio, 2002, P179

[5] Mutations of the BRAF gene in human cancer [J].

Davies, H ;

Bignell, GR ;

Cox, C ;

Stephens, P ;

Edkins, S ;

Clegg, S ;

Teague, J ;

Woffendin, H ;

Garnett, MJ ;

Bottomley, W ;

Davis, N ;

Dicks, N ;

Ewing, R ;

Floyd, Y ;

Gray, K ;

Hall, S ;

Hawes, R ;

Hughes, J ;

Kosmidou, V ;

Menzies, A ;

Mould, C ;

Parker, A ;

Stevens, C ;

Watt, S ;

Hooper, S ;

Wilson, R ;

Jayatilake, H ;

Gusterson, BA ;

Cooper, C ;

Shipley, J ;

Hargrave, D ;

Pritchard-Jones, K ;

Maitland, N ;

Chenevix-Trench, G ;

Riggins, GJ ;

Bigner, DD ;

Palmieri, G ;

Cossu, A ;

Flanagan, A ;

Nicholson, A ;

Ho, JWC ;

Leung, SY ;

Yuen, ST ;

Weber, BL ;

Siegler, HF ;

Darrow, TL ;

Paterson, H ;

Marais, R ;

Marshall, CJ ;

Wooster, R .

NATURE, 2002, 417 (6892) :949-954

[6]

FINK CA, 2005, 1 4 DISUBSTITUTED IS, P144

[7] Guilty as charged: B-RAF is a human oncogene [J].

Garnett, MJ ;

Marais, R .

CANCER CELL, 2004, 6 (04) :313-319

[8] Amination reactions of aryl halides with nitrogen-containing reagents mediated by palladium/imidazolium salt systems [J].

Grasa, GA ;

Viciu, MS ;

Huang, JK ;

Nolan, SP .

JOURNAL OF ORGANIC CHEMISTRY, 2001, 66 (23) :7729-7737

[9] Paradoxical activation of Raf by a novel Raf inhibitor [J].

Hall-Jackson, CA ;

Eyers, PA ;

Cohen, P ;

Goedert, M ;

Boyle, FT ;

Hewitt, N ;

Plant, H ;

Hedge, P .

CHEMISTRY & BIOLOGY, 1999, 6 (08) :559-568

[10] Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885 [J].

King, Alastair J. ;

Patrick, Denis R. ;

Batorsky, Roberta S. ;

Ho, Maureen L. ;

Do, Hieu T. ;

Zhang, Shu Yun ;

Kumar, Rakesh ;

Rusnak, David W. ;

Takle, Andrew K. ;

Wilson, David M. ;

Hugger, Erin ;

Wang, Lifu ;

Karreth, Florian ;

Lougheed, Julie C. ;

Lee, Jae ;

Chau, David ;

Stout, Thomas J. ;

May, Earl W. ;

Rominger, Cynthia M. ;

Schaber, Michael D. ;

Luo, Lusong ;

Lakdawala, Ami S. ;

Adams, Jerry L. ;

Contractor, Rooja G. ;

Smalley, Keiran S. M. ;

Herlyn, Meenhard ;

Morrissey, Michael M. ;

Tuveson, David A. ;

Huang, Pearl S. .

CANCER RESEARCH, 2006, 66 (23) :11100-11105

← 1 2 3 →