Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.

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Aronov AM, Baker C, Bemis GW, Cao J, Chen G, Ford PJ, Germann UA, Green J, Hale MR, Jacobs M, Janetka JW, Maltais F, Martinez-Botella G, Namchuk MN, Straub J, Tang Q, Xie X

Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.

J Med Chem. 2007 Mar 22;50(6):1280-7. Epub 2007 Feb 15.

PubMed ID

17300186 [ View in PubMed

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Abstract

The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Mitogen-activated protein kinase 1	P28482	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(S)-N-(1-(3-CHLORO-4-FLUOROPHENYL)-2-HYDROXYETHYL)-4-(4-(3-CHLOROPHENYL)-1H-PYRAZOL-3-YL)-1H-PYRROLE-2-CARBOXAMIDE	Mitogen-activated protein kinase 1	Ki (nM)	2	7.5	30	Details
N-BENZYL-4-[4-(3-CHLOROPHENYL)-1H-PYRAZOL-3-YL]-1H-PYRROLE-2-CARBOXAMIDE	Mitogen-activated protein kinase 1	Ki (nM)	86	7.5	30	Details
N-BENZYL-4-[4-(3-CHLOROPHENYL)-1H-PYRAZOL-3-YL]-1H-PYRROLE-2-CARBOXAMIDE	Mitogen-activated protein kinase 10	Ki (nM)	550	7.5	30	Details
N,N-DIMETHYL-4-(4-PHENYL-1H-PYRAZOL-3-YL)-1H-PYRROLE-2-CARBOXAMIDE	Mitogen-activated protein kinase 1	Ki (nM)	2300	7.5	30	Details