Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase

被引：27

作者：

Johnson, Christopher N. ^{[1
]}

Berdini, Valerio ^{[1
]}

Beke, Lijs ^{[2
]}

Bonnet, Pascal ^{[2
]}

Brehmer, Dirk ^{[2
]}

Coyle, Joseph E. ^{[1
]}

Day, Phillip J. ^{[1
]}

Frederickson, Martyn ^{[1
]}

Freyne, Eddy J. E. ^{[2
]}

Gilissen, Ron A. H. J. ^{[2
]}

Hamlett, Christopher C. F. ^{[1
]}

Howard, Steven ^{[1
]}

Meerpoel, Lieven ^{[2
]}

McMenamin, Rachel ^{[1
]}

Patel, Sahil ^{[1
]}

Rees, David C. ^{[1
]}

Sharff, Andrew ^{[1
]}

Sommen, Francois ^{[2
]}

Wu, Tongfei ^{[2
]}

Linders, Joannes T. M. ^{[2
]}

机构：

[1] Astex Pharmaceut, Cambridge CB4 0QA, England

[2] Janssen Res & Dev, B-2340 Beerse, Belgium

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 01期

关键词：

Maternal embryonic leucine zipper kinase; fragment-based drug design; structure-based optimization; ACTIVATED PROTEIN-KINASE; MELK; EXPRESSION; PROLIFERATION; TARGET; GROWTH; CELLS;

D O I：

10.1021/ml5001245

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 mu M) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.

引用

页码：25 / 30

页数：6

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