Inhibitors of Cdc25 phosphatases as anticancer agents: a patent review

Lavecchia, Antonio; Giovanni, Carmen Di; Novellino, Ettore

doi:10.1517/13543771003623232

Cited by 61 publications

(65 citation statements)

References 81 publications

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“…Protein phosphorylation and dephosphorylation are catalyzed by protein kinases and protein phosphatases, respectively [1]. The protein phosphatases can be divided into two different subclasses; the first class specifically hydrolyses serine/threonine phosphoesters whereas the second class is referred to as tyrosine phosphatases and specifically hydrolyses phosphotyrosine [2]. The tyrosine phosphatases also include a family of dual specificity phosphatases that hydrolyze both phosphotyrosines and serine/threonine phosphoesters; the cell division cycle 25 (CDC25) phosphatases are a subset among these dual specificity phosphatases [2].…”

Section: Introductionmentioning

confidence: 99%

“…The protein phosphatases can be divided into two different subclasses; the first class specifically hydrolyses serine/threonine phosphoesters whereas the second class is referred to as tyrosine phosphatases and specifically hydrolyses phosphotyrosine [2]. The tyrosine phosphatases also include a family of dual specificity phosphatases that hydrolyze both phosphotyrosines and serine/threonine phosphoesters; the cell division cycle 25 (CDC25) phosphatases are a subset among these dual specificity phosphatases [2]. This family includes CDC25A, CDC25B and CDC25C [3]; these three enzymes are important regulators of several steps in the cell cycle and they possibly have a role in the development of a variety of human malignancies [2,4].…”

Section: Introductionmentioning

confidence: 99%

“…The tyrosine phosphatases also include a family of dual specificity phosphatases that hydrolyze both phosphotyrosines and serine/threonine phosphoesters; the cell division cycle 25 (CDC25) phosphatases are a subset among these dual specificity phosphatases [2]. This family includes CDC25A, CDC25B and CDC25C [3]; these three enzymes are important regulators of several steps in the cell cycle and they possibly have a role in the development of a variety of human malignancies [2,4]. CDC25 inhibition is therefore considered as a possible therapeutic strategy in cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

et al. 2014

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Abstract:The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit OPEN ACCESSMolecules 2014, 19 18415 several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

et al. 2014

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“…This question could be of high interest in the light of the preparation of potent CDC25 inhibitors. 9,21,22 One of them, IRC-083864, is entered in clinical trial phase 2 under the name of Debio 0931. 22 In this study, we show that JAK2 V617F expression results in enhanced CDC25A expression and that CDC25 inhibition leads to a dramatic reduction of JAK2 V617F erythroid progenitor proliferation.…”

Section: Introductionmentioning

confidence: 99%

The cell cycle regulator CDC25A is a target for JAK2V617F oncogene

Gautier

Picard

Laurent

et al. 2012

Blood

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The JAK2 V617F mutation is present in the majority of patients with polycythemia vera and one-half of those with essential thrombocythemia and primary myelofibrosis. JAK2 V617F is a gain-of-function mutation resulting in constitutive JAK2 signaling involved in the pathogenesis of these diseases. JAK2 V617F has been shown to promote S-phase entry. Here, we demonstrate that the CDC25A phosphatase, a key regulator of the G1/S cell-cycle transition, is constitutively overexpressed in JAK2 V617F -positive cell lines, JAK2-mutated patient CD36 ؉ progenitors, and in vitro-differentiated proerythroblasts. Accordingly, CDC25A is overexpressed in BM and spleen of Jak2 V617F knock-in mice compared with wild-type littermates. By using murine FDC-P1-EPOR and human HEL and SET-2 cell lines, we found that JAK2 V617F -induced CDC25A upregulation was caused neither by increased CDC25A transcription or stability nor by the involvement of its upstream regulators Akt and MAPK. Instead, our results suggest that CDC25A is regulated at the translational level through STAT5 and the translational initiation factor eIF2␣. CDC25A inhibition reduces the clonogenic and proliferative potential of JAK2 V617F -expressing cell lines and erythroid progenitors while moderately affecting normal erythroid differentiation. These results suggest that CDC25A deregulation may be involved in hematopoietic cells expansion in JAK2 V617F IntroductionA unique somatic mutation, JAK2 V617F , recently was described in myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). [1][2][3][4] This mutation promotes cytokine independence in cell lines and is sufficient to induce MPNs in mouse models, suggesting that it represents a major molecular event in the pathogenesis of these diseases. 5,6 At the molecular level, JAK2 V617F leads to JAK2 tyrosine kinase autophosphorylation and constitutive activation of downstream cell signaling pathways, including STAT, MAPK/Erk, and PI3K. 1,4 Although these pathways are known to be involved in cell proliferation and survival, the link between JAK2 V617F and hematopoietic cell expansion remains not entirely understood.JAK2 V617F has been shown to promote G1/S cell cycle transition in parallel with p27 kip1 down-regulation and cyclin D2 induction in HEL and Ba/F3-EPOR cell lines. 7,8 Cell cycle progression is controlled by cyclin/cyclin-dependent kinase (CDK) complexes that are inactive when phosphorylated. One of the key regulators of the G1/S transition is CDC25A, a member of the CDC25 dual (Tyr/Thr) specificity phosphatase family. The CDC25 enzymes stimulate cell proliferation by dephosphorylating the 2 inhibitory residues of CDK1 and CDK2. 9 The main target of CDC25A is the cyclin E-or cyclin A-associated CDK2, whose activation is necessary for both the full completion of the G1 phase and DNA synthesis activation. It has been shown that CDC25A expression can be regulated by transcriptional factors such as E2F-1, 10 c-myc, 11 and STAT3. 12 Mor...

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“…[66][67][68] They are therefore considered as viable therapeutic targets, but despite a significant effort in the literature, only one pharmaceutical entity has entered clinical trials. [69] This is potentially due to the very small and narrow, hydrophilic active site pocket, which is particularly unsuitable to bind drug-like molecules. [70,71] However, a hotspot over 20 Å from the active site pocket was reported for cdc25B as crucial for binding to cdk substrates, and may potentially represent a new pocket to target for cdc25-cdk inhibition.…”

Section: Disadvantages Of Reversible Covalent Capturementioning

confidence: 99%

Kinetic Template‐Guided Tethering of Fragments

2012

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This thesis is composed of two separate projects: Kinetic Template-Guided Tethering of Fragments and Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1 Degradation after DNA Damage. Kinetic Template-Guided Tethering of FragmentsThe development of a novel methodology for the site-directed discovery of small molecule, protein-binding ligands is described. The protein of interest, with a cysteine thiol (either native or engineered) adjacent to the desired binding pocket, is incubated with mixtures of low molecular weight compounds (fragments) modified with either an acrylamide or a vinyl sulfonamide capture group. Any ligand within the mixture that binds within the pocket brings the capture group into close proximity with the cysteine thiol, promoting a conjugate addition reaction at an increased rate over the background reaction. The capture reaction is designed to be slow, such that during the time course of an experiment, no adduct formation is observed unless the reaction is templated by the protein. By this method, binding ligands are rapidly identified by mass spectrometry analysis of the crude reaction mixtures. The methodology has been termed 'kinetic template-guided tethering'. Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1Degradation after DNA Damage An inhibitor described within the literature was found to attenuate the reduction of cyclin D1 after DNA damage to cells. In order to implement a two-step chemical proteomics strategy to find the molecular target of this inhibitor, a synthesis of the compound with an alkyne appendage was required. The alkyne acts as a functional handle for attachment of a reporter molecule in cells via the Huisgen cycloaddition ('Click') reaction. The design and synthesis of this inhibitor with the alkyne appendage is described.

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Inhibitors of Cdc25 phosphatases as anticancer agents: a patent review

Abstract: Some Cdc25 inhibitors have suppressed in vivo the growth of human tumor xenografts in animals; this confirmed the validity of using Cdc25 phosphatase inhibition as an anticancer strategy, but side effects and toxicity remain to be investigated.

Cited by 61 publications

References 81 publications

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

The cell cycle regulator CDC25A is a target for JAK2V617F oncogene

Kinetic Template‐Guided Tethering of Fragments

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