PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer

Carpinelli, Patrizia; Ceruti, Roberta; Giorgini, Maria Laura; Cappella, Paolo; Gianellini, Laura; Croci, Valter; Degrassi, Anna; Texidó, Gemma; Rocchetti, Maurizio; Vianello, Paola; Rusconi, Luisa; Storici, Paola; Zugnoni, Paola; Arrigoni, Claudio; Soncini, Chiara; Alli, Cristina; Patton, Veronica; Marsiglio, Aurelio; Ballinari, Dario; Pesenti, Enrico; Fancelli, Daniele; Moll, Jürgen

doi:10.1158/1535-7163.mct-07-0444

Cited by 215 publications

(171 citation statements)

References 43 publications

(60 reference statements)

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“…3A and Supplementary Table S4, started the day after randomization. Tumor dimensions were measured regularly using Vernier calipers, and tumor growth inhibition (TGI) was calculated as previously described (29).…”

Section: Animal Efficacy Studiesmentioning

confidence: 99%

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Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC 50 . PHA-848125-treated cells show cell cycle arrest in G 1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243-54. ©2010 AACR.

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Section: Animal Efficacy Studiesmentioning

confidence: 99%

“…Tumor induction was done as previously described (29). Rats were randomized and introduced into the study when at least one mammary tumor attained a diameter of 0.5 cm.…”

Section: Animal Efficacy Studiesmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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“…Another Aurora kinase inhibitor, PHA-739358 [46], was also very active in vivo-in this case the authors extended the work beyond classic tumour xenografts to perhaps more relevant spontaneous tumour models and transgenic tumour models. When PHA-739358 was evaluated classic nude mouse xenograft models, significant growth inhibition was reported (up to 98% in HL60 xenografts dosed with 60 mg/ kg/day PHA-739358 i.v.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Mitotic drivers—inhibitors of the Aurora B Kinase

Keen

Taylor

2009

Cancer Metastasis Rev

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“…Danusertib (formally PHA-739358) [8,9], Scheme 1A, is a new, small ATP competitive molecule that inhibits Aurora kinases in vitro and in vivo [10]. Also, danusertib binds and inhibits with high affinity (IC 50 < 0.50 µM) several other tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA which are involved in the pathogenesis of a variety of cancers [11].…”

Section: Introductionmentioning

confidence: 99%

Electrochemical and spectrophotometric characterisation of protein kinase inhibitor and anticancer drug danusertib

Popa

Diculescu

2013

Electrochimica Acta

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 AbstractThe electrochemical oxidation mechanism of the anti-cancer drug and kinases inhibitor danusertib was studied by cyclic, differential pulse, square wave voltammetry and a glassy carbon electrode. Danusertib undergoes oxidation in a cascade mechanism and depending on the pH of the supporting electrolyte several oxidation peaks were observed. The number of electrons and protons involved in each oxidation step as well as the pK a ~ 10.0 were determined. The analytical determination of danusertib was carried out in pH = 7.0 by square wave voltammetry with LOD = 27.4 nM and UV-VIS spectrophotometry with LOD = 0.5 µM. Different electroactive centres of danusertib were identified through comparative studies with similar compounds such as imatinib and piperazine, and an oxidation mechanism of danusertib proposed.

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PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer

Cited by 215 publications

References 43 publications

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Mitotic drivers—inhibitors of the Aurora B Kinase

Electrochemical and spectrophotometric characterisation of protein kinase inhibitor and anticancer drug danusertib

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