Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose... more Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose activity depends on the binding with cyclins. Deregulated CDK activities have been reported in a majority of human cancers, representing potential therapeutic targets. This review provides preclinical and clinical (phase I/II) updates of promising therapeutic compounds targeting CDKs published between 2013 and 2016 EXPERT OPINION: First generation pan-CDK inhibitors showed marked toxicity in clinical trials and most compounds were discontinued. Despite their failure was ascribed also to inadequate patient selection rules, novel pan-CDK inhibitors have entered clinical trials with still poorly defined selection strategies. The most interesting results have been obtained with dual CDK4/6 inhibitors and through a more accurate evaluation of predictive biomarkers, suggesting the usefulness of CDK inhibitors for personalized treatment. The increased knowledge on the roles of CDKs in cell cycle and gene transcription suggests to review also the anticancer potential of first generation CDK inhibitors by defining more appropriate rules for patients engagement. Recent findings has highlighted CDK8 as a novel target for cancer treatment. Indeed some biomarkers for CDK8 inhibition sensitivity have already been proposed. CDK8 inhibition is also supposed to prevent cancer metastasis.
PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, s... more PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARγ modulators (SPPARγMs) as safer alternatives to PPARγ full agonists. This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARγMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARγ activation. Specifically, the in vivo glucose-lowering properties of the high-affinity SPPARγM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities. The patent (WO2014177593 A1) under discussion proposes enriching functional food p...
CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for... more CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for anticancer drug discovery. We recently identified NSC 119915 as a new quinonoid CDC25 inhibitor with potent anticancer activity. In order to discover more active analogs of NSC 119915, we performed a range of ligand-based chemoinformatic methods against the full ZINC drug-like subset and the NCI lead-like set. Nine compounds (3, 5-9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN. Compound 7 arrested melanoma cells in G2/M, causing a reduction of the protein levels of CDC25A and, more consistently, of CDC25C. Furthermore, an intrinsic apoptotic pathway was induced, which was mediated by ROS, because it was reverted in the presence of antioxidant N-acetyl-cysteine (NAC). Finally, 7 decreased the protein levels of phosphorylated Akt...
The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from ... more The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential.We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L.NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion.A subsequent hierarchical similarity search with NSC47924 led to the identification of addition...
Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPA... more Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPAR) is able to bind vitronectin, via a direct binding site. Furthermore, uPAR interacts with other cell surface receptors, such as integrins, receptor tyrosine kinases, and chemotaxis receptors, triggering cell-signaling pathways that promote tumor progression. The ability of uPAR to coordinate binding and degradation of extracellular matrix (ECM) and cell signaling makes it an attractive therapeutic target in cancer. We used structure-based virtual screening (SB-VS) to search for small molecules targeting the uPAR-binding site for vitronectin. Forty-one compounds were identified and tested on uPAR-negative HEK-293 epithelial cells transfected with uPAR (uPAR-293 cells), using the parental cell line transfected with the empty vector (V-293 cells) as a control. Compounds 6 and 37 selectively inhibited uPAR-293 cell adhesion to vitronectin and the resulting changes in cell morphology and si...
New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones... more New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.
New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5H-... more New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5H-benzopyrido[2,3-j]phenoxazin-5-ones (7-9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10-12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1-6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7-9 were scarcely active, whereas the corresponding benzo derivatives 10-12 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 10-12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase.
We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most poten... more We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most potent and selective ligand (SJ749) known to date. The model was built using the comparative protein modeling method, and it is consistent with experimental data. From this study, we identified two potentially important regions in the alpha5beta1 receptor that are peculiar to this integrin and might be worth considering for drug targeting.
Friedreich&am... more Friedreich's ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the mitochondrial protein frataxin. Here, we report findings that frataxin is degraded via the ubiquitin-proteasomal pathway and that it is ubiquitinated at residue K(147) in Calu-6 cells. A theoretical model of the frataxin-K(147)/Ub complex, constructed by combining bioinformatics interface predictions with information-driven docking, revealed a hitherto unnoticed, potential ubiquitin-binding domain in frataxin. Through structure-based virtual screening and cell-based assays, we discovered a novel small molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation. (+)-11 was synthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay. Follow-up scaffold-based searches resulted in the identification of a lead series with micromolar activity in disrupting the frataxin/Ub interaction. This study also suggests that frataxin could be a potential target for FRDA drug development.
The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introdu... more The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that pla... more The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Thus, the development of potent and selective inhibitors that target STAT3 is of interest especially in the cancer therapeutic area. This review updates new patents claiming STAT3 inhibitors and their uses published from 2011 to 2013. Pre-2011 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. The growing number of preclinical studies in numerous malignances as well as the first clinical trials of STAT3 inhibitors suggest that STAT3 remains a valid target for the treatment of human cancers as well as inflammatory diseases and/or autoimmune disorders. So, the future looks bright for patients because many new drugs are being developed and now combinations of STAT3 inhibitors with other targeted agents can diminish the resistance to traditional chemotherapy. These advances are expected to lead to further significant progress improving patient outcomes and quality of life.
The cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosp... more The cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases, the main gatekeepers of the eukaryotic cell division cycle. The three isoforms of Cdc25, including Cdc25A, Cdc25B and Cdc25C, appear to act on different cyclin-dependent kinase/cyclin complexes at different stages of the cell cycle. Overexpression of Cdc25A and/or Cdc25B, but not Cdc25C, has been detected in numerous cancers and is often correlated with a poor clinical prognosis. Thus, inhibition of these phosphatases may represent a promising therapeutic approach in oncology. The main focus of the present review is to describe the development of Cdc25 inhibitors over the years. We describe different compounds according to the decade of discovery and focus attention on molecules that were published in patents. Insight into the most clinically relevant therapeutic Cdc25 analogues that have been published in over 40 patents over the past 19 years. 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.
Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose... more Cell cycle and gene transcription are under the control of cyclin-dependent kinases (CDKs), whose activity depends on the binding with cyclins. Deregulated CDK activities have been reported in a majority of human cancers, representing potential therapeutic targets. This review provides preclinical and clinical (phase I/II) updates of promising therapeutic compounds targeting CDKs published between 2013 and 2016 EXPERT OPINION: First generation pan-CDK inhibitors showed marked toxicity in clinical trials and most compounds were discontinued. Despite their failure was ascribed also to inadequate patient selection rules, novel pan-CDK inhibitors have entered clinical trials with still poorly defined selection strategies. The most interesting results have been obtained with dual CDK4/6 inhibitors and through a more accurate evaluation of predictive biomarkers, suggesting the usefulness of CDK inhibitors for personalized treatment. The increased knowledge on the roles of CDKs in cell cycle and gene transcription suggests to review also the anticancer potential of first generation CDK inhibitors by defining more appropriate rules for patients engagement. Recent findings has highlighted CDK8 as a novel target for cancer treatment. Indeed some biomarkers for CDK8 inhibition sensitivity have already been proposed. CDK8 inhibition is also supposed to prevent cancer metastasis.
PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, s... more PPARγ is an essential regulator of lipid, glucose, and insulin metabolism. PPARγ full agonists, such as thiazolidinediones, are the mainstay drugs for the treatment of type 2 diabetes; however, undesirable clinical side effects have contributed to poor compliance with therapy and limited their full therapeutic potential. In the last few years, many efforts have been made in the discovery and development of selective PPARγ modulators (SPPARγMs) as safer alternatives to PPARγ full agonists. This application claims the plant-derived amorfrutins or their synthetic analogs as SPPARγMs with potential to exhibit glucose-lowering effects without provoking side effects associated with full PPARγ activation. Specifically, the in vivo glucose-lowering properties of the high-affinity SPPARγM amorfrutin B are described. Moreover, examples of this class of compounds exhibit interesting antiproliferative activities. The patent (WO2014177593 A1) under discussion proposes enriching functional food p...
CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for... more CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for anticancer drug discovery. We recently identified NSC 119915 as a new quinonoid CDC25 inhibitor with potent anticancer activity. In order to discover more active analogs of NSC 119915, we performed a range of ligand-based chemoinformatic methods against the full ZINC drug-like subset and the NCI lead-like set. Nine compounds (3, 5-9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN. Compound 7 arrested melanoma cells in G2/M, causing a reduction of the protein levels of CDC25A and, more consistently, of CDC25C. Furthermore, an intrinsic apoptotic pathway was induced, which was mediated by ROS, because it was reverted in the presence of antioxidant N-acetyl-cysteine (NAC). Finally, 7 decreased the protein levels of phosphorylated Akt...
The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from ... more The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential.We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L.NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion.A subsequent hierarchical similarity search with NSC47924 led to the identification of addition...
Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPA... more Besides focusing urokinase (uPA) proteolytic activity on the cell membrane, the uPA receptor (uPAR) is able to bind vitronectin, via a direct binding site. Furthermore, uPAR interacts with other cell surface receptors, such as integrins, receptor tyrosine kinases, and chemotaxis receptors, triggering cell-signaling pathways that promote tumor progression. The ability of uPAR to coordinate binding and degradation of extracellular matrix (ECM) and cell signaling makes it an attractive therapeutic target in cancer. We used structure-based virtual screening (SB-VS) to search for small molecules targeting the uPAR-binding site for vitronectin. Forty-one compounds were identified and tested on uPAR-negative HEK-293 epithelial cells transfected with uPAR (uPAR-293 cells), using the parental cell line transfected with the empty vector (V-293 cells) as a control. Compounds 6 and 37 selectively inhibited uPAR-293 cell adhesion to vitronectin and the resulting changes in cell morphology and si...
New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones... more New antiproliferative compounds, the 1-aryl-3-ethoxycarbonyl-pyrido[2,3-g]isoquinolin-5,10-diones (PIQDs, 1-7), were designed on the basis of a molecular model obtained by aligning the common quinolinquinone substructure of 5H-pyrido[3,2-a]phenoxazin-5-one (PPH) and some known anticancer agents. A Diels-Alder reaction between quinolin-5,8-dione (QD) and a 2-azadiene, formed by demolition of 2-aryl-1,3-thiazolidine ethyl esters (T compounds), was used to produce 1-7 and the isomeric 1-aryl-3-ethoxycarbonylpyrido[3,2-g]isoquinolin-5,10-diones (8-14). Two other compounds, the 3-amino-3-ethoxycarbonyldihydrothieno[2,3-g]quinolin-4,9-dione (15) and the 3-amino-3-ethoxycarbonyldihydrothieno[3,2-g]quinolin-4,9-dione (16), arising from a 1,4 Michael reaction of QD with a thiolate species formed by opening of T compounds, were recovered from the reaction mixture. The antiproliferative activity of 1-16 was evaluated against representative human liquid and solid neoplastic cell lines. The IC(50) of these compounds had median values in the range 2.00-0.01 microM, with 2-4 and 15 exhibiting significantly higher in vitro cytotoxic activity. Compound 2, also evaluated against KB subclones (KB(MDR), KB(7D), and KB(V20C)), was shown to be scarcely subject to the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. The noncovalent DNA-binding properties of PIQDs were examined using UV-vis and (1)H NMR spectroscopy experiments. Accordingly, these compounds were confirmed to have an ability to intercalate into double-stranded DNA by topoisomerase I superhelix unwinding assay. Interesting structure-activity relationships were found. Three important features seem to contribute to the cytotoxic activity of these anticancer ligands: (i) the DNA intercalating capability of the three-cyclic quinonic system, typical of this class of compounds, (ii) the position of the pendant phenyl ring that, according to the superimposition model, must occupy the same area of the corresponding benzo-fused ring A of PPH, and (iii) the effect of electron-withdrawing substituents on the phenyl ring, which can contribute improving the pi-pi stacking interactions between ligand and DNA base pairs. Besides, a mechanism of action suspected to involve topoisomerases could be hypothesized to interpret the antiproliferative activity of the thienoquinolindione 15, which can be regarded as a cyclic cysteine derivative.
New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5H-... more New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5H-benzopyrido[2,3-j]phenoxazin-5-ones (7-9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10-12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1-6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7-9 were scarcely active, whereas the corresponding benzo derivatives 10-12 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors pi-pi stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 10-12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase.
We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most poten... more We report a three-dimensional model of the alpha5beta1 integrin headgroup bound to the most potent and selective ligand (SJ749) known to date. The model was built using the comparative protein modeling method, and it is consistent with experimental data. From this study, we identified two potentially important regions in the alpha5beta1 receptor that are peculiar to this integrin and might be worth considering for drug targeting.
Friedreich&am... more Friedreich's ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the mitochondrial protein frataxin. Here, we report findings that frataxin is degraded via the ubiquitin-proteasomal pathway and that it is ubiquitinated at residue K(147) in Calu-6 cells. A theoretical model of the frataxin-K(147)/Ub complex, constructed by combining bioinformatics interface predictions with information-driven docking, revealed a hitherto unnoticed, potential ubiquitin-binding domain in frataxin. Through structure-based virtual screening and cell-based assays, we discovered a novel small molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation. (+)-11 was synthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay. Follow-up scaffold-based searches resulted in the identification of a lead series with micromolar activity in disrupting the frataxin/Ub interaction. This study also suggests that frataxin could be a potential target for FRDA drug development.
The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introdu... more The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S-4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy.
The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that pla... more The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Thus, the development of potent and selective inhibitors that target STAT3 is of interest especially in the cancer therapeutic area. This review updates new patents claiming STAT3 inhibitors and their uses published from 2011 to 2013. Pre-2011 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. The growing number of preclinical studies in numerous malignances as well as the first clinical trials of STAT3 inhibitors suggest that STAT3 remains a valid target for the treatment of human cancers as well as inflammatory diseases and/or autoimmune disorders. So, the future looks bright for patients because many new drugs are being developed and now combinations of STAT3 inhibitors with other targeted agents can diminish the resistance to traditional chemotherapy. These advances are expected to lead to further significant progress improving patient outcomes and quality of life.
The cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosp... more The cell division cycle 25 (Cdc25) family of proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases, the main gatekeepers of the eukaryotic cell division cycle. The three isoforms of Cdc25, including Cdc25A, Cdc25B and Cdc25C, appear to act on different cyclin-dependent kinase/cyclin complexes at different stages of the cell cycle. Overexpression of Cdc25A and/or Cdc25B, but not Cdc25C, has been detected in numerous cancers and is often correlated with a poor clinical prognosis. Thus, inhibition of these phosphatases may represent a promising therapeutic approach in oncology. The main focus of the present review is to describe the development of Cdc25 inhibitors over the years. We describe different compounds according to the decade of discovery and focus attention on molecules that were published in patents. Insight into the most clinically relevant therapeutic Cdc25 analogues that have been published in over 40 patents over the past 19 years. 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.
Uploads
Papers by Antonio Lavecchia