title: A combination strategy to inhibit Pim-1: synergism between noncompetitive and ATP-competitive inhibitors.
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.
authors: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors: Mattia
authors: M
authors: Mori
authors: Cristina
authors: C
authors: Tintori
authors: Robert Selwyne Arul
authors: RS
authors: Christopher
authors: Marco
authors: M
authors: Radi
authors: Silvia
authors: S
authors: Schenone
authors: Francesca
authors: F
authors: Musumeci
authors: Chiara
authors: C
authors: Brullo
authors: Patrizia
authors: P
authors: Sanità
authors: Simona
authors: S
authors: Delle Monache
authors: Adriano
authors: A
authors: Angelucci
authors: Miroslava
authors: M
authors: Kissova
authors: Emmanuele
authors: E
authors: Crespan
authors: Giovanni
authors: G
authors: Maga
authors: Maurizio
authors: M
authors: Botta
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017434:Protein Structure, Tertiary; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011994:Recombinant Proteins; D013844:Thiazoles; C004483:2-aminothiazole; C030374:indole; D000255:Adenosine Triphosphate; D051573:Proto-Oncogene Proteins c-pim-1