The aurora kinase inhibitor CCT137690 downregulates MYCN and sensitizes MYCN-amplified neuroblastoma in vivo. 2011

Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
Cancer Research UK, Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, United Kingdom.

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.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D008938 Mitosis A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species. M Phase, Mitotic,Mitotic M Phase,M Phases, Mitotic,Mitoses,Mitotic M Phases,Phase, Mitotic M,Phases, Mitotic M
D009447 Neuroblastoma A common neoplasm of early childhood arising from neural crest cells in the sympathetic nervous system, and characterized by diverse clinical behavior, ranging from spontaneous remission to rapid metastatic progression and death. This tumor is the most common intraabdominal malignancy of childhood, but it may also arise from thorax, neck, or rarely occur in the central nervous system. Histologic features include uniform round cells with hyperchromatic nuclei arranged in nests and separated by fibrovascular septa. Neuroblastomas may be associated with the opsoclonus-myoclonus syndrome. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2099-2101; Curr Opin Oncol 1998 Jan;10(1):43-51) Neuroblastomas
D009687 Nuclear Proteins Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. Nucleolar Protein,Nucleolar Proteins,Nuclear Protein,Protein, Nuclear,Protein, Nucleolar,Proteins, Nuclear,Proteins, Nucleolar
D011123 Polyploidy The chromosomal constitution of a cell containing multiples of the normal number of CHROMOSOMES; includes triploidy (symbol: 3N), tetraploidy (symbol: 4N), etc. Polyploid,Polyploid Cell,Cell, Polyploid,Cells, Polyploid,Polyploid Cells,Polyploidies,Polyploids
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D005784 Gene Amplification A selective increase in the number of copies of a gene coding for a specific protein without a proportional increase in other genes. It occurs naturally via the excision of a copy of the repeating sequence from the chromosome and its extrachromosomal replication in a plasmid, or via the production of an RNA transcript of the entire repeating sequence of ribosomal RNA followed by the reverse transcription of the molecule to produce an additional copy of the original DNA sequence. Laboratory techniques have been introduced for inducing disproportional replication by unequal crossing over, uptake of DNA from lysed cells, or generation of extrachromosomal sequences from rolling circle replication. Amplification, Gene
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

Related Publications

Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
February 2022, Cancer science,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
March 2021, Nature cancer,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
October 2012, Pediatric blood & cancer,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
January 2014, Journal of experimental & clinical cancer research : CR,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
June 2021, Neoplasia (New York, N.Y.),
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
June 2022, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
January 2021, Anti-cancer agents in medicinal chemistry,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
January 2014, Journal of pediatric surgery,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
October 2020, International journal of cancer,
Amir Faisal, and Lynsey Vaughan, and Vassilios Bavetsias, and Chongbo Sun, and Butrus Atrash, and Sian Avery, and Yann Jamin, and Simon P Robinson, and Paul Workman, and Julian Blagg, and Florence I Raynaud, and Suzanne A Eccles, and Louis Chesler, and Spiros Linardopoulos
August 2015, Molecular oncology,
Copied contents to your clipboard!