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JX401, A p38 Inhibitor Containing a 4-Benzylpiperidine Motif, Identified via a Novel Screening System in Yeast

Jexys Pharmaceuticals Ltd., Jerusalem, Israel (Y.F., A.S., E.R.B., D.E.); the Department of Biological Chemistry, the Alexander Silberman Institute of Life Sciences, the Hebrew University of Jerusalem, Jerusalem, Israel (D.E., R.D., I.M.); and Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel (S.G., E.B.)

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 p38 via a high throughput screen using yeast cells. p38 is hyperactive in inflammatory diseases, and various indications suggest that its inhibition would reverse inflammation. However, there are currently no p38 inhibitors in clinical use. Because the human p38 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 p38 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 p38 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.

Address correspondence to: Dr. David Engelberg, Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. E-mail: engelber{at}cc.huji.ac.il