3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 1. Lead Finding

Pevarello, Paolo; Brasca, Maria Gabriella; Amici, Raffaella; Orsini, Paolo; Traquandi, Gabriella; Corti, Luca; Piutti, Claudia; Sansonna, Pietro; Villa, M.; Pierce, Betsy S.; Pulici, Maurizio; Giordano, Patrizia; Martina, Katia; Fritzen, Edward L.; Nugent, Richard A.; Casale, Elena; Cameron, Alexander D.; Ciomei, Marina; Roletto, Fulvia; Isacchi, Antonella; Fogliatto, Gianpaolo; Pesenti, Enrico; Pastori, Wilma; Marsiglio, Aurelio; Leach, Karen L.; Clare, Paula M.; Fiorentini, Francesco; Varasi, Mario; Vulpetti, Anna; Warpehoski, Martha A.

doi:10.1021/jm031145u

Cited by 157 publications

(163 citation statements)

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“…including recently described CDK2/cyclin A inhibitors (Pevarello et al, 2004). Inhibition of ILK with QLT-0267 in HEK293 cells transfected with either the luciferase reporter construct TOPFlash, or the control reporter construct FOPFlash, showed a specific inhibition of Wnt3a-induced activation of Tcf/Lef transcription factor (Figure 2b).…”

Section: Resultsmentioning

confidence: 63%

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

2006

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The Wnt gene family encodes secreted signaling molecules that play important roles in tumorgenesis and embryogenesis. The canonical Wnt signaling pathway regulates target gene expression via the stabilization and nuclear translocation of the cytoplasmic pool of b-catenin. The activation of integrin-linked kinase (ILK) is also known to regulate the stabilization and subsequent nuclear translocation of b-catenin in several epithelial cell models. We now report that molecular and pharmacological inhibition of ILK activity in mammalian cells directly modulates Wnt signaling by suppressing the stabilization and nuclear translocation of b-catenin, as well as b-catenin/Lefmediated transcription. Inhibition of ILK activity, but not phosphatidylinositol-3 kinase (PI3K) or MEK activities suppresses nuclear b-catenin stabilization in cells stably expressing Wnt3a as well as in cells exposed to either Wnt3a conditioned media or purified Wnt3a. Furthermore, ILK inhibition reverses the Wnt3a-induced suppression of b-catenin phosphorylation that accompanies b-catenin stabilization. In addition, we show that ILK can be identified in a complex with Wnt pathway components such as adenomatous polyposis coli and GSK-3. Upon treatment of L cells with Wnt3a-CM, glycogen synthase kinase-3 (GSK-3b) becomes highly phosphorylated on Ser 9, which is completely abolished upon inhibition of ILK activity. However, acute exposure of L cells to purified Wnt3a does not result in the stimulation of GSK-3b Ser 9 phosphorylation, despite b-catenin stabilization. Together our data demonstrate that ILK activity can modulate acute Wnt3a mediated b-catenin phosphorylation, stabilization and nuclear activation in a PI3K-independent manner, as well as the more prolonged PI3K-dependent secondary effects of Wnt signaling on GSK-3 phosphorylation. Finally, we suggest that a novel small molecule inhibitor of ILK, QLT-0267, may be a useful tool in the regulation of pathological Wnt signaling.

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Section: Resultsmentioning

confidence: 63%

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

2006

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“…Cells were collected, fixed, and stained as previously described (28). Cytofluorimetric analysis was done using a FACSCalibur (BD Biosciences), and cell cycle phases were calculated by ModFit 3.0 (Verity Software House).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…Staining was done as previously described (28). Percentage of BrdUrd incorporation was calculated counting positive nuclei from a total of 200 cells.…”

Section: Immunocytochemical Analysismentioning

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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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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“…A dataset 38) comprising of 42, 3-aminopyrazoles having inhibitory activity against CDK2/cyclin A was selected for the development of model for the present investigation. The basic structure of these compounds is presented in Fig.…”

Section: Model Developmentmentioning

confidence: 99%

“…38) One of the key CDK2 substrates is the E2F-1 protein itself, of which the turnover and activity is induced by phosphorylation by CDK2/cyclin A. This leads to higher than normal levels of E2F, which have been found to induce apoptosis.…”

mentioning

confidence: 99%

Topochemical Models for Prediction of Anti-tumor Activity of 3-Aminopyrazoles

Bajaj

Самби

Мадан³

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Graph theory has been used for modeling chemical structures, that is, chemical compounds, intermediates, changes and mechanisms.1) Over the past decades graph-based molecular structure descriptors have developed into a quite active field. In these applications a molecular structure is identified to a graph, with vertices representing non-H atoms and edges representing chemical bonds.2) During the last decade the interest in the problem of computer-aided design of organic structures with prescribed properties has significantly increased.3) Today, the information feeding the drug design effort is increasingly quantitative, based upon recent developments in molecular structure description, combinatorial mathematics, statistics, and computer simulations. 4) In chemistry, a graph represents the topology of a molecule in the sense that it depicts the pattern of connectedness of atoms in the molecule, being, at the same time, independent of such metric aspects of molecular structure as equilibrium distance between nuclei, bond angles, etc. 5) Topological indices or graph invariants are the single numbers for characterization of molecular structures. 6) In recent years a large number of topological indices have been reported and utilized for chemical documentation, isomer discrimination, study of molecular complexity, chirality, similarity/dissimilarity, QSAR/ QSPR, drug design and database selection, lead optimization, rational combinatorial library design and for deriving multilinear regression models.7-10) Though a large number of topological indices have been reported in literature but only some of them have been successfully employed in SAR studies. Notable amongst these are Wiener's index, 11,12) Hosoya's index, 13,14) Randic's molecular connectivity index, c, 15) the higher-order connectivity indices, n c, for the paths of length n defined by Kier and Hall,16) Balaban's index, J, [17][18][19][20] Zagreb group parameters, M 1 and M 2 , 21) eccentric connectivity index, [22][23][24][25][26] eccentric adjacency index 27,28) and superpendentic index. 29) Topochemical indices are the topological indices derived from the chemical graphs and modified so as to take into consideration the presence and relative position of heteroatom. Topochemical indices that have been reported and used for SAR studies include atomic molecular connectivity index, 30) eccentric adjacency topochemical index, 31) Wiener's topochemical index 32,33) and superadjacency topochemical index. 34,35) The importance of cyclin-dependent kinases (CDKs) in cell cycle regulation, their interaction with oncogenes and tumor suppressors, and their frequent deregulation in human tumors, has encouraged an active search for agents capable of perturbing the function of CDKs.36) Therefore, inhibition of cyclin-dependent kinases is a theme of major interest in current anti-cancer agents' research. Different classes of chemical inhibitors of these enzymes have been identified during the past decade and the structural basis of inhibition has been elucidated by X-ra...

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3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 1. Lead Finding

Cited by 157 publications

References 34 publications

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

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

Topochemical Models for Prediction of Anti-tumor Activity of 3-Aminopyrazoles

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