Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation

被引：389

作者：

Sun, Qi ^{[1
]}

Burke, Jason P. ^{[1
]}

Phan, Jason ^{[1
]}

Burns, Michael C. ^{[1
]}

Olejniczak, Edward T. ^{[1
]}

Waterson, Alex G. ^{[2
]}

Lee, Taekyu ^{[1
]}

Rossanese, Olivia W. ^{[1
]}

Fesik, Stephen W. ^{[1
]}

机构：

[1] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2012年 / 51卷 / 25期

基金：

美国国家卫生研究院;

关键词：

fragment-based screening; GTPases; K-Ras inhibitors; ligand design; NMR spectroscopy; KRAS MUTATIONS; ONCOGENES; CANCER;

D O I：

10.1002/anie.201201358

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

Looking for fragments: A fragment-based screen using NMR spectroscopy was applied to discover ligands that bind to the GTPase K-Ras and modulate the activity of the nucleotide exchange factor Sos. Structural data on how these fragment-derived hits bind to the guanosine diphosphate-K-Ras complex (see picture) provides a starting point for the future discovery of drugs that target K-Ras activation and signaling. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

引用

页码：6140 / 6143

页数：4

共 17 条

[1]

Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].

Arkin, MR ;

Wells, JA .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317

[2]

The structural basis of the activation of Ras by Sos [J].

Boriack-Sjodin, PA ;

Margarit, SM ;

Bar-Sagi, D ;

Kuriyan, J .

NATURE, 1998, 394 (6691) :337-343

[3]

BOS JL, 1989, CANCER RES, V49, P4682

[4]

Essential role for oncogenic Ras in tumour maintenance [J].

Chin, L ;

Tam, A ;

Pomerantz, J ;

Wong, M ;

Holash, J ;

Bardeesy, N ;

Shen, Q ;

O'Hagan, R ;

Pantginis, J ;

Zhou, H ;

Horner, JW ;

Cordon-Cardo, C ;

Yancopoulos, GD ;

DePinho, RA .

NATURE, 1999, 400 (6743) :468-472

[5]

A decade of fragment-based drug design: strategic advances and lessons learned [J].

Hajduk, Philip J. ;

Greer, Jonathan .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (03) :211-219

[6]

Hallmarks of Cancer: The Next Generation [J].

Hanahan, Douglas ;

Weinberg, Robert A. .

CELL, 2011, 144 (05) :646-674

[7]

Fragment-based screening using X-ray crystallography and NMR spectroscopy [J].

Jhoti, Harren ;

Cleasby, Anne ;

Verdonk, Marcel ;

Williams, Glyn .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2007, 11 (05) :485-493

[8]

Kigawa Takanori, 2002, Journal of Structural and Functional Genomics, V2, P29, DOI 10.1023/A:1013203532303

[9]

Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers [J].

Laghi, L ;

Orbetegli, O ;

Bianchi, P ;

Zerbi, A ;

Di Carlo, V ;

Boland, CR ;

Malesci, A .

ONCOGENE, 2002, 21 (27) :4301-4306

[10]

Non-redundancy within the RAS oncogene family: Insights into mutational disparities in cancer [J].

Lau, Ken S. ;

Haigis, Kevin M. .

MOLECULES AND CELLS, 2009, 28 (04) :315-320

← 1 2 →