Patent Watch

July 29, 2013

These ERK2 inhibitors may block tumor-forming pathways. J. Lim and co-inventors introduce compounds represented by formula 1 that inhibit extracellular-signal–regulated kinase 2 (ERK2). These compounds may be useful for treating a broad spectrum of cancers.

ERK2, also known as mitogen-activated protein kinase 1 (MAPK1), is a serine–threonine kinase that is expressed in most mammalian tissues. It is part of the Ras-Raf-ERK signal transduction cascade, which is activated by a cascade of phosphorylation events and influences cellular processes such as proliferation, differentiation, and survival.

Mutations of Ras and BRAF (a serine–threonine kinase of the Raf family) and frequent activation of the ERK/MAPK pathway have been detected in many cancerous tumors. Therefore, inhibiting the ERK signaling pathway is an attractive target for treating in a broad spectrum of human tumors.

The compounds described in this patent application that inhibit ERK2 activity may potentially provide useful treatments of several forms of cancers, including melanoma and pancreatic, thyroid, colorectal, lung, breast, and ovarian cancers.

General structure 1 and three examples of ERK2 inhibitors

The inventors describe the synthesis of 701 examples of formula 1. Three of these compounds are shown in the figure. The inventors evaluated the compounds by the active human ERK2 (hERK2) and active mouse ERK2 (mERK2) activity assays. The IC50 data for the three examples are given in the table.

  Activity assay
Example hERK2
IC50 (nM)
mERK2
IC50 (nM)
2
0.1524
0.2857
3 0.1524 0.2045
4 0.2223 0.8512

(Merck Sharp and Dohme [Rahway, NJ]. WIPO Publication 2013063214, May2, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

View patent information from CAplus(SM) database.

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