2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.

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Argiriadi MA, Ericsson AM, Harris CM, Banach DL, Borhani DW, Calderwood DJ, Demers MD, Dimauro J, Dixon RW, Hardman J, Kwak S, Li B, Mankovich JA, Marcotte D, Mullen KD, Ni B, Pietras M, Sadhukhan R, Sousa S, Tomlinson MJ, Wang L, Xiang T, Talanian RV

2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.

Bioorg Med Chem Lett. 2010 Jan 1;20(1):330-3. doi: 10.1016/j.bmcl.2009.10.102. Epub 2009 Oct 29.

PubMed ID
19919896 [ View in PubMed
]
Abstract

MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
StaurosporineMAP kinase-activated protein kinase 2IC 50 (nM)700N/AN/ADetails
StaurosporineMAP kinase-activated protein kinase 2IC 50 (nM)660N/AN/ADetails
StaurosporineMAP kinase-activated protein kinase 2IC 50 (nM)1700N/AN/ADetails
StaurosporineMAP kinase-activated protein kinase 2IC 50 (nM)3400N/AN/ADetails