title: The Pim kinases: new targets for drug development.
abstract: The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.
authors.affiliation: Cancer Therapy and Research Center, Institute for Drug Development, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA. swordsr@uthscsa.edu
authors.forename: Ronan
authors.initials: R
authors.lastname: Swords
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelly
authors.forename: Jennifer
authors.initials: J
authors.lastname: Carew
authors.forename: Stefan
authors.initials: S
authors.lastname: Nawrocki
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: John
authors.initials: J
authors.lastname: Sarantopoulos
authors.forename: David
authors.initials: D
authors.lastname: Bearss
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545188:SGI 1776; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim