Potent and selective pyrazole-based inhibitors of B-Raf kinase

被引：64

作者：

Hansen, Joshua D. ^{[1
]}

Grina, Jonas ^{[1
]}

Newhouse, Brad ^{[1
]}

Welch, Mike ^{[1
]}

Topalov, George ^{[1
]}

Littman, Nicole ^{[1
]}

Callejo, Michele ^{[1
]}

Gloor, Susan ^{[1
]}

Martinson, Matthew ^{[1
]}

Laird, Ellen ^{[1
]}

Brandhuber, Barbara J. ^{[1
]}

Vigers, Guy ^{[1
]}

Morales, Tony ^{[1
]}

Woessner, Rich ^{[1
]}

Randolph, Nikole ^{[1
]}

Lyssikatos, Joseph ^{[2
]}

Olivero, Alan ^{[2
]}

机构：

[1] Array BioPharma, Lead Optimizat, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 16期

关键词：

B-Raf; Raf; RAF; RAS; MEK; ERK; V600E; inhibitors; cancer;

D O I：

10.1016/j.bmcl.2008.07.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4692 / 4695

页数：4

共 12 条

[1] N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck:: Indazoles as phenol isosteres with improved pharmacokinetics [J].

Bamborough, Paul ;

Angell, Richard M. ;

Bhamra, Inder ;

Brown, David ;

Bull, James ;

Christopher, John A. ;

Cooper, Anthony W. J. ;

Fazal, Lynsey H. ;

Giordano, Ilaria ;

Hind, Lucy ;

Patel, Vipulkumar K. ;

Ranshaw, Lisa E. ;

Sims, Martin J. ;

Skone, Philip A. ;

Smith, Kathryn J. ;

Vickerstaff, Emma ;

Washington, Melanie .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (15) :4363-4368

[2] BRAF mutation in papillary thyroid carcinoma [J].

Cohen, J ;

Xing, MZ ;

Mambo, E ;

Guo, ZM ;

Wu, GG ;

Trink, B ;

Beller, U ;

Westra, WH ;

Ladenson, PW ;

Sidransky, D .

JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2003, 95 (08) :625-627

[3] 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

[4]

DESBORDES P, 1994, Patent No. 9429300

[5] COSMIC 2005 [J].

Forbes, S ;

Clements, J ;

Dawson, E ;

Bamford, S ;

Webb, T ;

Dogan, A ;

Flanagan, A ;

Teague, J ;

Wooster, R ;

Futreal, PA ;

Stratton, MR .

BRITISH JOURNAL OF CANCER, 2006, 94 (02) :318-322

[6] Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors [J].

Hoshino, R ;

Chatani, Y ;

Yamori, T ;

Tsuruo, T ;

Oka, H ;

Yoshida, O ;

Shimada, Y ;

Ari-i, S ;

Wada, H ;

Fujimoto, J ;

Kohno, M .

ONCOGENE, 1999, 18 (03) :813-822

[7] Selective Raf inhibition in cancer therapy [J].

Khazak, Vladimir ;

Astsaturov, Igor ;

Serebriiskii, Ilya G. ;

Golemis, Erica A. .

EXPERT OPINION ON THERAPEUTIC TARGETS, 2007, 11 (12) :1587-1609

[8]

Laird E., 2006, Inhibitor enzyme activity was determined utilizing full-length B-RafV600E. Inhibition of basal ERK phosphorylation in Malme-3M cells was used as the mechanistic cellular assay, Patent No. [2006/084015 A2, 2006084015]

[9] The identification of potent and selective imidazole-based inhibitors of B-Raf kinase [J].

Takle, AK ;

Brown, MJB ;

Davies, S ;

Dean, DK ;

Francis, G ;

Gaiba, A ;

Hird, AW ;

King, FD ;

Lovell, PJ ;

Naylor, A ;

Reith, AD ;

Steadman, JG ;

Wilson, DM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (02) :378-381

[10] Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors.: 1.: 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones [J].

Wallace, EM ;

Lyssikatos, J ;

Blake, JF ;

Seo, J ;

Yang, HW ;

Yeh, TC ;

Perrier, M ;

Jarski, H ;

Marsh, V ;

Poch, G ;

Livingston, MG ;

Otten, J ;

Hingorani, G ;

Woessner, R ;

Lee, P ;

Winkler, J ;

Koch, K .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (02) :441-444

← 1 2 →