Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors.

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Olla S, Manetti F, Crespan E, Maga G, Angelucci A, Schenone S, Bologna M, Botta M

Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors.

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1512-6. doi: 10.1016/j.bmcl.2009.01.005. Epub 2009 Jan 9.

PubMed ID

19179076 [ View in PubMed

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Abstract

Pim1 belongs to a family of serine/threonine kinases, which is involved in the control of cell growth, differentiation, and apoptosis. Pim1 plays a pivotal role in cytokine signaling and is implicated in the development of a large number of tumors, representing a very attractive target for anticancer therapy. In this work, we applied a virtual screening protocol aimed at identifying small molecules able to inhibit Pim1 activity. The search of novel inhibitors was performed through a structure-based molecular modeling approach, taking advantage of the availability of the three-dimensional crystal structure of inhibitors bound to Pim1. Starting from the knowledge of protein-ligand complexes, the software LigandScout was used to generate pharmacophoric models, in turn used as queries to perform a virtual screening of databases, followed by docking experiments. As a result, a restricted set of candidates for biological testing was identified. Finally, among the six compounds selected as potential inhibitors of Pim1, two candidates endowed with a significant activity against Pim1 emerged. Interestingly, one of these compounds has a chemical scaffold different from inhibitors previously identified.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Staurosporine	Serine/threonine-protein kinase pim-1	IC 50 (nM)	10	N/A	N/A	Details