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15 July 2007
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Although kinases of the PIM family have been suggested as targets for the development of drugs with anticancer activity, selective inhibitors that would validate PIM as a target for clinical intervention have not yet been identified. Here, Pogacic and colleagues have identified imidazo[1,2-b]pyridazines as selective and potent inhibitors of PIM1 and PIM3 kinases, using in vitro binding as well as enzyme kinetic assays. Analysis of the high-resolution crystal structure of a complex with one of the lead compounds revealed that these inhibitors form no classical hydrogen bonds with the kinase hinge region. Formation of hydrogen bonds to the hinge backbone is a hallmark for the binding of ATP and ATP mimetic inhibitors to the kinase active site, rendering imidazo[1,2-b]pyridazines as ATP competitive but not ATP mimetic PIM inhibitors. This binding mode and screening of a focused library resulted in the identification of selective PIM inhibitors that showed only weak cross-reactivity with one other kinase in a panel of 50 serine/threonine kinases screened. The authors show that imidazo[1,2-b]pyridazines also inhibit PIM in cells and have in vitro antileukemic activity using primary cells from acute myelogenous leukemia patients. For details, see the article by Pogacic and colleagues on page 6916 of this issue.Close Modal - PDF Icon PDF LinkTable of Contents
ISSN 0008-5472
EISSN 1538-7445
Journal Archive
Cancer Research (1941-Present; volumes 1-current)
(ISSN 0008-5472) Published twice monthly since 1987. From 1941-1986, published monthly.The American Journal of Cancer (1931-1940; volumes 15-40)
(ISSN 0099-7374) Published quarterly in 1931, bimonthly in 1932, and monthly from 1933 to 1940. The journal changed title to Cancer Research in 1941.The Journal of Cancer Research (1916-1930); volumes 1-14)
(ISSN 0099-7013) Published quarterly from 1916 through 1930 (publication was suspended from November 1922 to March 1924). The journal changed title to The American Journal of Cancer in 1931.Table of Contents
Reviews
Meeting Report
Priority Reports
Molecular Biology, Pathobiology, and Genetics
Proteomics-Based Identification of Proteins Secreted in Apical Surface Fluid of Squamous Metaplastic Human Tracheobronchial Epithelial Cells Cultured by Three-Dimensional Organotypic Air-Liquid Interface Method
Seung-Wook Kim; Kyounga Cheon; Chang-Hoon Kim; Joo-Heon Yoon; David H. Hawke; Ryuji Kobayashi; Ludmila Prudkin; Ignacio I. Wistuba; Reuben Lotan; Waun Ki Hong; Ja Seok Koo
The E2F-Regulated Gene Chk1 Is Highly Expressed in Triple-Negative Estrogen Receptor−/Progesterone Receptor−/HER-2− Breast Carcinomas
Lieve Verlinden; Isabelle Vanden Bempt; Guy Eelen; Maria Drijkoningen; Ilse Verlinden; Kathleen Marchal; Christiane De Wolf-Peeters; Marie-Rose Christiaens; Luc Michiels; Roger Bouillon; Annemieke Verstuyf
MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis
Katsumi Sakamoto; Yohei Tominaga; Kazumi Yamauchi; Yoshimichi Nakatsu; Kunihiko Sakumi; Kaoru Yoshiyama; Akinori Egashira; Shinobu Kura; Takashi Yao; Masazumi Tsuneyoshi; Hisaji Maki; Yusaku Nakabeppu; Teruhisa Tsuzuki
Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma
Samuel Singer; Nicholas D. Socci; Grazia Ambrosini; Elliot Sambol; Penelope Decarolis; Yuhsin Wu; Rachael O'Connor; Robert Maki; Agnes Viale; Chris Sander; Gary K. Schwartz; Cristina R. Antonescu
Cell, Tumor, and Stem Cell Biology
IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo
Benjamin Drogat; Patrick Auguste; Duc Thang Nguyen; Marion Bouchecareilh; Raphael Pineau; Josephine Nalbantoglu; Randal J. Kaufman; Eric Chevet; Andréas Bikfalvi; Michel Moenner
ERM/ETV5 Up-regulation Plays a Role during Myometrial Infiltration through Matrix Metalloproteinase-2 Activation in Endometrial Cancer
Marta Monge; Eva Colas; Andreas Doll; Marta Gonzalez; Antonio Gil-Moreno; Jesus Planaguma; Maite Quiles; Maria Antonia Arbos; Angel Garcia; Josep Castellvi; Marta Llaurado; Marina Rigau; Hafid Alazzouzi; Jordi Xercavins; Francesc Alameda; Jaume Reventos; Miguel Abal
Eukaryotic Translation Initiation Factor 4E–Induced Progression of Primary Human Mammary Epithelial Cells along the Cancer Pathway Is Associated with Targeted Translational Deregulation of Oncogenic Drivers and Inhibitors
Ola Larsson; Shunan Li; Olga A. Issaenko; Svetlana Avdulov; Mark Peterson; Karen Smith; Peter B. Bitterman; Vitaly A. Polunovsky
Experimental Therapeutics, Molecular Targets, and Chemical Biology
Tumor Paint: A Chlorotoxin:Cy5.5 Bioconjugate for Intraoperative Visualization of Cancer Foci
Mandana Veiseh; Patrik Gabikian; S-Bahram Bahrami; Omid Veiseh; Miqin Zhang; Robert C. Hackman; Ali C. Ravanpay; Mark R. Stroud; Yumiko Kusuma; Stacey J. Hansen; Deborah Kwok; Nina M. Munoz; Raymond W. Sze; William M. Grady; Norman M. Greenberg; Richard G. Ellenbogen; James M. Olson
The RET Kinase Inhibitor NVP-AST487 Blocks Growth and Calcitonin Gene Expression through Distinct Mechanisms in Medullary Thyroid Cancer Cells
Nagako Akeno-Stuart; Michelle Croyle; Jeffrey A. Knauf; Roberta Malaguarnera; Donata Vitagliano; Massimo Santoro; Christine Stephan; Konstantina Grosios; Markus Wartmann; Robert Cozens; Giorgio Caravatti; Doriano Fabbro; Heidi A. Lane; James A. Fagin
Immunology
A Polyepitope DNA Vaccine Targeted to Her-2/ErbB-2 Elicits a Broad Range of Human and Murine CTL Effectors to Protect against Tumor Challenge
Antonio Scardino; Maurizio Alimandi; Pierpaolo Correale; Steven G. Smith; Roberto Bei; Hüseyin Firat; Maria Grazia Cusi; Olivier Faure; Stephanie Graf-Dubois; Giulia Cencioni; Jordan Marrocco; Salem Chouaib; François A. Lemonnier; Andrew Michael Jackson; Kostas Kosmatopoulos
Clinical Research
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