title: The aurora kinase inhibitor CCT137690 downregulates MYCN and sensitizes MYCN-amplified neuroblastoma in vivo.
abstract: Aurora kinases regulate key stages of mitosis including centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. Aurora A and B kinase overexpression has also been associated with various human cancers, and as such, they have been extensively studied as novel antimitotic drug targets. Here, we characterize the Aurora kinase inhibitor CCT137690, a highly selective, orally bioavailable imidazo[4,5-b]pyridine derivative that inhibits Aurora A and B kinases with low nanomolar IC(50) values in both biochemical and cellular assays and exhibits antiproliferative activity against a wide range of human solid tumor cell lines. CCT137690 efficiently inhibits histone H3 and transforming acidic coiled-coil 3 phosphorylation (Aurora B and Aurora A substrates, respectively) in HCT116 and HeLa cells. Continuous exposure of tumor cells to the inhibitor causes multipolar spindle formation, chromosome misalignment, polyploidy, and apoptosis. This is accompanied by p53/p21/BAX induction, thymidine kinase 1 downregulation, and PARP cleavage. Furthermore, CCT137690 treatment of MYCN-amplified neuroblastoma cell lines inhibits cell proliferation and decreases MYCN protein expression. Importantly, in a transgenic mouse model of neuroblastoma that overexpresses MYCN protein and is predisposed to spontaneous neuroblastoma formation, this compound significantly inhibits tumor growth. The potent preclinical activity of CCT137690 suggests that this inhibitor may benefit patients with MYCN-amplified neuroblastoma.
authors: Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, United Kingdom.
authors: Amir
authors: A
authors: Faisal
authors: Lynsey
authors: L
authors: Vaughan
authors: Vassilios
authors: V
authors: Bavetsias
authors: Chongbo
authors: C
authors: Sun
authors: Butrus
authors: B
authors: Atrash
authors: Sian
authors: S
authors: Avery
authors: Yann
authors: Y
authors: Jamin
authors: Simon P
authors: SP
authors: Robinson
authors: Paul
authors: P
authors: Workman
authors: Julian
authors: J
authors: Blagg
authors: Florence I
authors: FI
authors: Raynaud
authors: Suzanne A
authors: SA
authors: Eccles
authors: Louis
authors: L
authors: Chesler
authors: Spiros
authors: S
authors: Linardopoulos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D005784:Gene Amplification / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C551619:3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo(4,5-b)pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole; D000970:Antineoplastic Agents; D007093:Imidazoles; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases