title: Identification of quinones as novel PIM1 kinase inhibitors.
abstract: PIM1 is a proto-oncogene encoding the serine/threonine PIM1 kinase. PIM1 kinase plays important roles in regulating aspects of cell cycle progression, apoptosis resistance, and has been implicated in the development of such malignancies as prostate cancer and acute myeloid leukemia among others. Knockout of PIM1 kinase in mice has been shown to be non-lethal without any obvious phenotypic changes, making it an attractive therapeutic target. Our investigation of anthraquinones as kinase inhibitors revealed a series of quinone analogs showing high selectivity for inhibition of the PIM kinases. Molecular modeling studies were used to identify key interactions and binding poses of these compounds within the PIM1 binding pocket. Compounds 1, 4, 7 and 9 inhibited the growth of DU-145 prostate cancer cell lines with a potency of 8.21μM, 4.06μM, 3.21μM and 2.02μM.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schroeder
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Navneet
authors.initials: N
authors.lastname: Goyal
authors.affiliation: Cell and Molecular Biology Core Facility, Xavier University of Louisiana, New Orleans, LA 70125, USA.
authors.forename: Melyssa
authors.initials: M
authors.lastname: Bratton
authors.affiliation: Cell and Molecular Biology Core Facility, Xavier University of Louisiana, New Orleans, LA 70125, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Townley
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Pham
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Phan
authors.initials: P
authors.lastname: Tram
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Treasure
authors.initials: T
authors.lastname: Stone
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Geathers
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA. Electronic address: jsridhar@xula.edu.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011809:Quinones; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Emodin; Pim1 kinase; Prostate cancer; Quinones; Selectivity profile