Characterization of Covalent Pyrazolopyrimidine-MKK7 Complexes and a Report on a Unique DFG-in/Leu-in Conformation of Mitogen-Activated Protein Kinase Kinase 7 (MKK7)

被引：12

作者：

Wolle, Patrik ^{[1
,2
]}

Engel, Julian ^{[1
,3
]}

Smith, Steven ^{[1
,4
]}

Goebel, Lisa ^{[1
,2
]}

Hennes, Elisabeth ^{[1
,5
]}

Lategahn, Jonas ^{[1
,2
,6
]}

Rauh, Daniel ^{[1
,2
]}

机构：

[1] TU Dortmund Univ, Fac Chem & Chem Biol, Otto Hahn Str 4a, D-44227 Dortmund, Germany

[2] ZIW, DDHD, D-44227 Dortmund, Germany

[3] Lead Discovery Ctr GmbH, Otto Hahn Str 15, D-44227 Dortmund, Germany

[4] Agap2 Frankfurt, Bockenheimer Landstr 72, D-60323 Frankfurt, Germany

[5] Max Planck Inst Mol Physiol, Otto Hahn Str 11, D-44227 Dortmund, Germany

[6] PearlRiver Bio GmbH, Otto Hahn Str 15, D-44227 Dortmund, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 11期

关键词：

DRUG-RESISTANCE; INHIBITORS; EGFR; DISCOVERY; INSIGHTS;

D O I：

10.1021/acs.jmedchem.9b00472

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pyrazolopyrimidines are well-established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor or Bruton's tyrosine kinase, and we recently described their potential in targeting mitogen-activated protein kinase kinase 7 (MKK7). Herein, we report the structure activity relationship of pyrazolopyrimidine-based MKK7 inhibitors and solved several complex crystal structures to gain insights into their binding mode. In addition, we present two structures of apo-MKK7, exhibiting a DFG-out and an unprecedented DFG-in/Leu-in conformation.

引用

页码：5541 / 5546

页数：6

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