Novel Mps1 kinase inhibitors: From purine to pyrrolopyrimidine and quinazoline leads

被引：15

作者：

Bursavich, Matthew G. ^{[1
]}

Dastrup, David ^{[1
]}

Shenderovich, Mark ^{[1
]}

Yager, Kraig M. ^{[1
]}

Cimbora, Daniel M. ^{[2
]}

Williams, Brandi ^{[2
]}

Kumar, D. Vijay ^{[1
]}

机构：

[1] Myrexis Inc, Med Chem, Salt Lake City, UT 84108 USA

[2] Myrexis Inc, Vitro Pharmacol, Salt Lake City, UT 84108 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 24期

关键词：

Mps1; TTK; Protein kinase inhibitors; Scaffold hopping; Conformational restriction; Structure-based design; Cancer; Purines; Pyrrolopyrimidines; Quinazoline; POTENT;

D O I：

10.1016/j.bmcl.2013.10.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：6829 / 6833

页数：5

共 17 条

[1] Ligand efficiency indices as guideposts for drug discovery [J].

Abad-Zapatero, C ;

Metz, JT .

DRUG DISCOVERY TODAY, 2005, 10 (07) :464-469

[2]

[Anonymous], ALL NEWL PREP COMP W

[3]

[Anonymous], 2011, IM WER MAD ACC DISC

[4]

[Anonymous], 2008, J MED CHEM

[5] Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines [J].

Bursavich, MG ;

Lombardi, S ;

Gilbert, AM .

ORGANIC LETTERS, 2005, 7 (19) :4113-4116

[6] Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors [J].

Caldarelli, Marina ;

Angiolini, Mauro ;

Disingrini, Teresa ;

Donati, Daniele ;

Guanci, Marco ;

Nuvoloni, Stefano ;

Posteri, Helena ;

Quartieri, Francesca ;

Silvagni, Marco ;

Colombo, Riccardo .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (15) :4507-4511

[7] Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex [J].

Hewitt, Laura ;

Tighe, Anthony ;

Santaguida, Stefano ;

White, Anne M. ;

Jones, Clifford D. ;

Musacchio, Andrea ;

Green, Stephen ;

Taylor, Stephen S. .

JOURNAL OF CELL BIOLOGY, 2010, 190 (01) :25-34

[8] Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit [J].

Huang, Haomin ;

Hittle, James ;

Zappacosta, Francesca ;

Annan, Roland S. ;

Hershko, Avram ;

Yen, Timothy J. .

JOURNAL OF CELL BIOLOGY, 2008, 183 (04) :667-680

[9] Mps1 phosphorylates borealin to control aurora B activity and chromosome alignment [J].

Jelluma, Nannette ;

Brenkman, Arjan B. ;

van den Broek, Niels J. F. ;

Cruijsen, Carin W. A. ;

van Osch, Maria H. J. ;

Lens, Susanne M. A. ;

Medema, Rene H. ;

Kops, Geert J. P. L. .

CELL, 2008, 132 (02) :233-246

[10] Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors [J].

Kumar, D. Vijay ;

Hoarau, Christophe ;

Bursavich, Matthew ;

Slattum, Paul ;

Gerrish, David ;

Yager, Kraig ;

Saunders, Michael ;

Shenderovich, Mark ;

Roth, Bruce L. ;

McKinnon, Rena ;

Chan, Ashley ;

Cimbora, Daniel M. ;

Bradford, Chad ;

Reeves, Leslie ;

Patton, Scott ;

Papac, Damon I. ;

Williams, Brandi L. ;

Carlson, Robert O. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (13) :4377-4385

← 1 2 →