title: SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation.
abstract: OBJECTIVE
  Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes.
  
  
  METHODS
  By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1.
  
  
  RESULTS
  SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability.
  
  
  CONCLUSIONS
  Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.
authors: University "Magna Graecia" of Catanzaro, Dept. of "Scienze della Salute", Catanzaro, Italy.
authors: Lucia
authors: L
authors: D'Antona
authors: Rosario
authors: R
authors: Amato
authors: Cristina
authors: C
authors: Talarico
authors: Francesco
authors: F
authors: Ortuso
authors: Miranda
authors: M
authors: Menniti
authors: Vincenzo
authors: V
authors: Dattilo
authors: Rodolfo
authors: R
authors: Iuliano
authors: Francesco
authors: F
authors: Gigliotti
authors: Anna
authors: A
authors: Artese
authors: Giosuè
authors: G
authors: Costa
authors: Silvia
authors: S
authors: Schenone
authors: Francesca
authors: F
authors: Musumeci
authors: Claudia
authors: C
authors: Abbruzzese
authors: Lorenzo
authors: L
authors: Botta
authors: Francesco
authors: F
authors: Trapasso
authors: Stefano
authors: S
authors: Alcaro
authors: Marco G
authors: MG
authors: Paggi
authors: Nicola
authors: N
authors: Perrotti
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D061986:MCF-7 Cells; D009336:Necrosis; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017874:Immediate-Early Proteins; D007328:Insulin; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D000099184:Serum-Glucocorticoid Regulated Kinases; C000603764:SI113 compound; C497206:MDM2 protein, human