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ChemMedChem. 2013 Mar;8(3):484-96. doi: 10.1002/cmdc.201200480.

A combination strategy to inhibit Pim-1: synergism between noncompetitive and ATP-competitive inhibitors.

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  • 1Dipartimento di Biotecnologie, Chimica e Farmacia, Universit√† degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.

Abstract

Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure-activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP-competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance.

Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
23436791
[PubMed - indexed for MEDLINE]
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