Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia

被引：75

作者：

Liu, Jing ^{[1
]}

Yang, Chao ^{[1
]}

Simpson, Catherine ^{[1
]}

DeRyckere, Deborah ^{[4
]}

Van Deusen, Amy ^{[1
]}

Miley, Michael J. ^{[2
]}

Kireev, Dmitri ^{[1
]}

Norris-Drouin, Jacqueline ^{[1
]}

Sather, Susan ^{[4
]}

Hunter, Debra ^{[3
]}

Korboukh, Victoria K. ^{[1
]}

Patel, Hari S. ^{[1
]}

Janzen, William P. ^{[1
]}

Machius, Mischa ^{[2
]}

Johnson, Gary L. ^{[2
,3
]}

Earp, H. Shelton ^{[2
,3
]}

Graham, Douglas K. ^{[4
]}

Frye, Stephen V. ^{[1
,3
]}

Wang, Xiaodong ^{[1
]}

机构：

[1] Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Dept Med, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[4] Univ Colorado Denver, Sch Med, Dept Pediat, Aurora, CO 80045 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 02期

关键词：

Mer inhibitors; acute lymphoblastic leukemia; pyrazolopyrimidines; chemosensitizer; TYROSINE KINASE; PROTOONCOGENE; EXPRESSION; SCAFFOLDS;

D O I：

10.1021/ml200239k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further act as chemosensitizers increasing efficacy and reducing toxicities of current ALL regimens. We have applied a structure-based design approach to discover novel small molecule Mer kinase inhibitors. Several pyrazolopyrimidine derivatives effectively inhibit Mer kinase activity at subnanomolar concentrations. Furthermore, the lead compound shows a promising selectivity profile against a panel of 72 kinases and has excellent pharmacokinetic properties. We also describe the crystal structure of the complex between the lead compound and Mer, opening new opportunities for further optimization and new template design.

引用

页码：129 / 134

页数：6

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