Potent and Selective Aurora Inhibitors Identified by the Expansion of a Novel Scaffold for Protein Kinase Inhibition

Fancelli, Daniele; Berta, Daniela; Bindi, Simona; Cameron, Alexander D.; Cappella, Paolo; Carpinelli, Patrizia; Catana, Cornel; Forte, Barbara; Giordano, Patrizia; Giorgini, Maria Laura; Mantegani, Sergio; Marsiglio, Aurelio; Meroni, M.; Moll, Jürgen; Pittalà, Valeria; Roletto, Fulvia; Severino, D.; Soncini, Chiara; Storici, Paola; Tonani, R.; Varasi, Mario; Vulpetti, Anna; Vianello, Paola

doi:10.1021/jm049076m

Cited by 143 publications

(128 citation statements)

References 15 publications

(29 reference statements)

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“…9,19 Small molecule inhibitors of pan-Aurora (-A and -B) and Aurora-B kinases are undergoing evaluation in clinical trials in patients with MM and other cancers 9,20,[25][26][27] ; however, these inhibitors of pan-Aurora kinases induce a phenotype consistent with Aurora-B, rather than Aurora-A, inhibition. 9,20,25,28,29 MLN8237 is the first orally available small molecule selective inhibitor of Aurora-A kinase, which is currently in early-phase clinical testing in patients with advanced solid tumors and acute myelogenous leukemia. In this study, we assess the in vitro and in vivo anti-MM activity of MLN8237 in preclinical models of human MM to provide the framework for its use, alone and in combination with conventional and novel anti-MM agents, to improve patient outcome in MM.…”

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confidence: 99%

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

Görgün

Calabrese

Hideshima

et al. 2010

Blood

243

164

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Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/ additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P ‫؍‬ .007) and overall survival was significantly increased (P < . IntroductionMultiple myeloma (MM) is a B-cell disease characterized by accumulation of malignant plasma cells in the bone marrow (BM), bone lesions, and immunodeficiency. Genetic analysis shows that approximately 55% to 60% of MM patients have a hyperdiploid karyotype, which confers a better prognosis than nonhyperdiploid disease. 1 The most frequent chromosomal abnormalities observed in nonhyperdiploid MM are translocations between immunoglobulin heavy chain gene located on chromosome 14q32 and an oncogene chromosome 11q13 (CYCLIN D1), 4p16.3 (FGFR3 and MMSET), 6p21 (CYCLIN D3), 16q23 (MAF), or 20q11 (MAFB); or less frequently, the immunoglobulin light chain locus (2p12, or 22q11). 2 During cell proliferation, activation of each cell-cycle phase is dependent on the progress and completion of the previous one. Regulation of the cell cycle involves detecting and repairing genetic damage, as well as controlling various checkpoints to prevent uncontrolled cell division. MM cells are further influenced by the BM microenvironment because adhesion of MM cells to extracellular-matrix proteins supports cell adhesion-mediated drug resistance. In addition, binding of MM cells to BM accessory cells induces secretion of cytokines, which further promote growth, survival, and migration of tumor cells, as well as resistance to conventional chemotherapy. 2,3 Aberrant or overexpression of D-type cyclins is ubiquitous in MM, 4,5 and Aurora kinases regulate cell-cycle checkpoints 6 and cell cycle-regulatory molecules, including cyclins and cyclindependent kinases. [7][8][9] Aurora serine/threonine kinases localize in the centrosome and play a crucial role in cell division by regulating chromatid segregation in mitotic cells 10 ; moreover, defective chromatid segregation causes genetic instability, leading to tumorigenesis. 11 They were first identified in Xenopus Eg2, yeast Ipl1, and Drosophila aurora. The human genome expresses 3 members of the mitotic Aurora kinase family: Aurora-A serine/threonine kinases, Aurora-B serine/threonine kinases, and Aurora-C s...

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confidence: 99%

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

Görgün

Calabrese

Hideshima

et al. 2010

Blood

243

164

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“…In earlier publications, a number of quinazoline-based series have been described as Aurora kinase inhibitors [2,22,[42][43][44] . Particularly, the p-benzamidoanilinoquinazoline series was shown to inhibit Aurora A and Aurora B equipotently.…”

Section: Discussionmentioning

confidence: 99%

Structural studies of B-type Aurora kinase inhibitors using computational methods

et al. 2010

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“…Danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. IT has also been reported to have some synergistic qualities while being used in combination with Imatinib in CML patients [Fancelli et al 2005].…”

Section: Pha-739358mentioning

confidence: 99%

Recent advances in the development of Aurora kinases inhibitors in hematological malignancies

Choudary

Barr

Friedberg

2015

Therapeutic Advances in Hematology

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Over the last two decades, since the discovery of Drosophila mutants in 1995, much effort has been made to understand Aurora kinase biology. Three mammalian subtypes have been identified thus far which include the Aurora A, B and C kinases. These regulatory proteins specifically work at the cytoskeleton and chromosomal structures between the kinetochores and have vital functions in the early phases of the mitotic cell cycle. Today, there are multiple phase I and phase II clinical trials as well as numerous preclinical studies taking place looking at Aurora kinase inhibitors in both hematologic and solid malignancies. This review focuses on the preclinical and clinical development of Aurora kinase inhibitors in hematological malignancy and discusses their therapeutic potential.

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Potent and Selective Aurora Inhibitors Identified by the Expansion of a Novel Scaffold for Protein Kinase Inhibition

Cited by 143 publications

References 15 publications

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

Structural studies of B-type Aurora kinase inhibitors using computational methods

Recent advances in the development of Aurora kinases inhibitors in hematological malignancies

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