JX401, a p38α inhibitor containing a 4-benzylpiperidine motif, identified via a novel screening system in yeast

Yael Friedmann, Anat Shriki, Estelle R. Bennett, Stella Golos, Ron Diskin, Irit Marbach, Eyal Bengal, David Engelberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

In vivo screening of compounds for potential pharmacological activity is more advantageous than in vitro screening. In vivo screens eliminate the isolation of compounds that cannot cross biological membranes, are cytotoxic, or are not specific to the target. However, animal-based or even cell-based systems are usually expensive, time-consuming, and laborious. Here we describe the identification of inhibitors of the mitogen-activated protein kinase p38α via a high throughput screen using yeast cells. p38α is hyperactive in inflammatory diseases, and various indications suggest that its inhibition would reverse inflammation. However, there are currently no p38α inhibitors in clinical use. Because the human p38α imposes severe growth retardation when expressed in yeast, we screened a library of 40,000 randomly selected small molecules for compounds that would restore a normal growth rate. We identified two compounds; both share a structural motif of 4-benzylpiperidine, and both were shown to be efficient and selective p38α inhibitors in vitro. They were also active in mammalian cells, as manifested by their ability to reversibly inhibit myoblast differentiation. Thus, the yeast screen identified efficient and specific p38α inhibitors that are capable of crossing biological membranes, are not toxic, and function in mammalian cells. The rapid and cost-efficient high-throughput screening used here could be applied for isolation of inhibitors of various targets.

Original languageAmerican English
Pages (from-to)1395-1405
Number of pages11
JournalMolecular Pharmacology
Volume70
Issue number4
DOIs
StatePublished - 2006

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