Csaba Szántai-kis - Academia.edu (original) (raw)
Papers by Csaba Szántai-kis
Current Medicinal Chemistry, 2006
Epidermal Growth Factor Receptor (EGFR) is a high priority target in anticancer drug research. Th... more Epidermal Growth Factor Receptor (EGFR) is a high priority target in anticancer drug research. Thousands of very effective EGFR inhibitors have been developed in the last decade. The known inhibitors are originated from a very diverse chemical space but--without exception--all of them act at the Adenosine TriPhosphate (ATP) binding site of the enzyme. We have collected all of the diverse inhibitor structures and the relevant biological data obtained from comparable assays and built prediction oriented Quantitative Structure-Activity Relationship (QSAR) which models the ATP binding pocket's interactive surface from the ligand side. We describe a QSAR method with automatic Variable Subset Selection (VSS) by Genetic Algorithm (GA) and goodness-of-prediction driven QSAR model building, resulting an externally validated EGFR inhibitory model built from pIC50 values of a diverse structural set of 623 EGFR inhibitors. Repeated Trainings/Evaluations (RTE) were used to obtain model fitness values and the effectiveness of VSS is amplified by using predictive ability scores of descriptors. Numerous models were generated by different methods and viable models were collected. Then, intensive RTE were applied to identify ultimate models for external validations. Finally, suitable models were validated by statistical tests. Since we use calculated molecular descriptors in the modeling, these models are suitable for virtual screening for obtaining novel potential EGFR inhibitors.
ACS Medicinal Chemistry Letters, 2014
Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a sub... more Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.
Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance... more Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 mM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-b-D-ribose 2 0epimerase, DprE1, required for arabinan synthesis.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2014
P ulmonary hypertension (PH) is a progressive disease resulting from increased pulmonary vascular... more P ulmonary hypertension (PH) is a progressive disease resulting from increased pulmonary vascular resistance. PH is resistant to current therapies and is characterized by excessive vascular cell proliferation, inward remodeling, rarefaction, and a loss of compliance of pulmonary blood vessels. 1-3 Increased resistance to blood flow and more rigid blood vessels leads to failure of the right ventricle (RV) and eventual death. Furthermore, PH is more frequent in women than men and, if untreated, has a survival time of <5 years postdiagnosis. 4,5 Reactive oxygen species (ROS) have been proposed as a pathogenic mechanism underlying the vascular remodeling observed in PH. However, the source, cellular origin, and functional significance of ROS in PH remain poorly defined. Elevated levels of ROS in PH are the net result of increased production and decreased degradation, and there is evidence for both mechanisms in the cause of elevated pulmonary pressure. 6-10 The major intracellular sources of ROS include the mitochondria, aberrant oxygenase activity, and the NADPH oxidase family of oxidases (Nox). 11,12 The human genome encodes 5 Nox isoforms and 4 of these, Nox1, Nox2, Nox4, and Nox5, are expressed in vascular cells (although Nox5 is not present in the genomes of rats and mice). In comparison with other sources of ROS, Nox enzymes are regarded as Objective-Pulmonary hypertension (PH) is a progressive disease arising from remodeling and narrowing of pulmonary arteries (PAs) resulting in high pulmonary blood pressure and ultimately right ventricular failure. Elevated production of reactive oxygen species by NADPH oxidase 4 (Nox4) is associated with increased pressure in PH. However, the cellular location of Nox4 and its contribution to aberrant vascular remodeling in PH remains poorly understood. Therefore, we sought to identify the vascular cells expressing Nox4 in PAs and determine the functional relevance of Nox4 in PH. Approach and Results-Elevated expression of Nox4 was detected in hypertensive PAs from 3 rat PH models and human PH using qualititative real-time reverse transcription polymerase chain reaction, Western blot, and immunofluorescence.
ASSAY and Drug Development Technologies, 2005
Kinase inhibitors are in the front line of modern drug research where mostly three technologies a... more Kinase inhibitors are in the front line of modern drug research where mostly three technologies are used for hit and lead finding: HTS of random libraries, 3D design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) technology is based on a knowledge base approach where focused libraries around 1 selected cores are used to generate a pharmacophore model. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All of the compounds in our NCL library are stored in a big unified SQL (Structured Query Language) database along with their measured and calculated physicochemical and ADME and toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Drug-likeness of all the compounds can be visualized with the widely accepted calculated Lipinski parameters. Biochemical kinase inhibitory on selected cloned kinase enzymes for a few hundred compound sets from NCL can provide enough biological data for rational computerized design of new analogues based on our pharmacophore model generating 3DNET4W TM QSPAR (Quantitative Structure-Property/Activity Relationships) approach. Using this pharmacophore modelling approach and the ADMET filters we can preselect the synthesizable compounds for hit and lead optimisation.
Tuberculosis, 2015
Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance... more Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Nested Chemical Library™ using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 μM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays.
Current Signal Transduction Therapy, 2006
Signal transduction therapy has become one of the most important areas of drug research. Signalin... more Signal transduction therapy has become one of the most important areas of drug research. Signaling disorders represent a major cause for the pathological states and many of the recently identified validated target molecules of drug research are signal transduction related macromolecules, mostly kinases. Rational drug design is aimed to achieve the selective inhibition of distinct pathologically relevant signaling enzymes or
Current Medicinal Chemistry, 2008
Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistan... more Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.
ASSAY and Drug Development Technologies, 2005
Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies a... more Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique, proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All the compounds in our NCL library are stored in a big unified Structured Query Language database along with their measured and calculated physicochemical and ADME/toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Biochemical kinase inhibitory assays on selected, cloned kinase enzymes for a few hundred NCL compound sets can provide sufficient biological data for rational computerized design of new analogues, based on our pharmacophore model-generating 3DNET4W QSPAR (quantitative structure-property/activity relationships) approach. Using this pharmacophore modeling approach and the ADMET filters, we can preselect synthesizable compounds for hit-and-lead optimization. Starting from this point and integrating the information from QSPAR, high-quality leads can be generated within a small number of optimization cycles. Applying NCL technology we have developed lead compounds for several validated kinase targets.
Current Medicinal Chemistry, 2006
Epidermal Growth Factor Receptor (EGFR) is a high priority target in anticancer drug research. Th... more Epidermal Growth Factor Receptor (EGFR) is a high priority target in anticancer drug research. Thousands of very effective EGFR inhibitors have been developed in the last decade. The known inhibitors are originated from a very diverse chemical space but--without exception--all of them act at the Adenosine TriPhosphate (ATP) binding site of the enzyme. We have collected all of the diverse inhibitor structures and the relevant biological data obtained from comparable assays and built prediction oriented Quantitative Structure-Activity Relationship (QSAR) which models the ATP binding pocket's interactive surface from the ligand side. We describe a QSAR method with automatic Variable Subset Selection (VSS) by Genetic Algorithm (GA) and goodness-of-prediction driven QSAR model building, resulting an externally validated EGFR inhibitory model built from pIC50 values of a diverse structural set of 623 EGFR inhibitors. Repeated Trainings/Evaluations (RTE) were used to obtain model fitness values and the effectiveness of VSS is amplified by using predictive ability scores of descriptors. Numerous models were generated by different methods and viable models were collected. Then, intensive RTE were applied to identify ultimate models for external validations. Finally, suitable models were validated by statistical tests. Since we use calculated molecular descriptors in the modeling, these models are suitable for virtual screening for obtaining novel potential EGFR inhibitors.
ACS Medicinal Chemistry Letters, 2014
Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a sub... more Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of the hepatocyte growth factor receptor (c-Met) gene. Although several EGFR and c-Met inhibitors have been reported, potent dual EGFR/c-Met inhibitors, which can overcome this latter resistance mechanism, have hitherto not been published and have not reached clinical trials. In the present study we have identified dual EGFR/c-Met inhibitors and designed novel N-[4-(quinolin-4-yloxy)-phenyl]-biarylsulfonamide derivatives, which inhibit the c-Met receptor and both the wild-type and the activating mutant EGFR kinases in nanomolar range. We have demonstrated by Western blot analysis that compound 10 inhibits EGFR and c-Met phosphorylation at cellular level and effectively inhibits viability of the NSCLC cell lines.
Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance... more Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find antimycobacterial scaffolds, we screened a kinase inhibitor library of more than 12,000 compounds using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and a target-based assay with the protein kinase PknA. Seventeen "hits" came from the whole cell-based screening approach, from which three displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 mM and were non-mutagenic and non-cytotoxic. Two of these hits were specific for M. tuberculosis versus C. glutamicum and none of them was found to inhibit the essential serine/threonine protein kinases, PknA and PknB present in both bacteria. One of the most active hits, VI-18469, had a benzoquinoxaline pharmacophore while another, VI-9376, is structurally related to a new class of antimycobacterial agents, the benzothiazinones (BTZ). Like the BTZ, VI-9376 was shown to act on the essential enzyme decaprenylphosphoryl-b-D-ribose 2 0epimerase, DprE1, required for arabinan synthesis.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2014
P ulmonary hypertension (PH) is a progressive disease resulting from increased pulmonary vascular... more P ulmonary hypertension (PH) is a progressive disease resulting from increased pulmonary vascular resistance. PH is resistant to current therapies and is characterized by excessive vascular cell proliferation, inward remodeling, rarefaction, and a loss of compliance of pulmonary blood vessels. 1-3 Increased resistance to blood flow and more rigid blood vessels leads to failure of the right ventricle (RV) and eventual death. Furthermore, PH is more frequent in women than men and, if untreated, has a survival time of <5 years postdiagnosis. 4,5 Reactive oxygen species (ROS) have been proposed as a pathogenic mechanism underlying the vascular remodeling observed in PH. However, the source, cellular origin, and functional significance of ROS in PH remain poorly defined. Elevated levels of ROS in PH are the net result of increased production and decreased degradation, and there is evidence for both mechanisms in the cause of elevated pulmonary pressure. 6-10 The major intracellular sources of ROS include the mitochondria, aberrant oxygenase activity, and the NADPH oxidase family of oxidases (Nox). 11,12 The human genome encodes 5 Nox isoforms and 4 of these, Nox1, Nox2, Nox4, and Nox5, are expressed in vascular cells (although Nox5 is not present in the genomes of rats and mice). In comparison with other sources of ROS, Nox enzymes are regarded as Objective-Pulmonary hypertension (PH) is a progressive disease arising from remodeling and narrowing of pulmonary arteries (PAs) resulting in high pulmonary blood pressure and ultimately right ventricular failure. Elevated production of reactive oxygen species by NADPH oxidase 4 (Nox4) is associated with increased pressure in PH. However, the cellular location of Nox4 and its contribution to aberrant vascular remodeling in PH remains poorly understood. Therefore, we sought to identify the vascular cells expressing Nox4 in PAs and determine the functional relevance of Nox4 in PH. Approach and Results-Elevated expression of Nox4 was detected in hypertensive PAs from 3 rat PH models and human PH using qualititative real-time reverse transcription polymerase chain reaction, Western blot, and immunofluorescence.
ASSAY and Drug Development Technologies, 2005
Kinase inhibitors are in the front line of modern drug research where mostly three technologies a... more Kinase inhibitors are in the front line of modern drug research where mostly three technologies are used for hit and lead finding: HTS of random libraries, 3D design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) technology is based on a knowledge base approach where focused libraries around 1 selected cores are used to generate a pharmacophore model. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All of the compounds in our NCL library are stored in a big unified SQL (Structured Query Language) database along with their measured and calculated physicochemical and ADME and toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Drug-likeness of all the compounds can be visualized with the widely accepted calculated Lipinski parameters. Biochemical kinase inhibitory on selected cloned kinase enzymes for a few hundred compound sets from NCL can provide enough biological data for rational computerized design of new analogues based on our pharmacophore model generating 3DNET4W TM QSPAR (Quantitative Structure-Property/Activity Relationships) approach. Using this pharmacophore modelling approach and the ADMET filters we can preselect the synthesizable compounds for hit and lead optimisation.
Tuberculosis, 2015
Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance... more Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Nested Chemical Library™ using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 μM and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays.
Current Signal Transduction Therapy, 2006
Signal transduction therapy has become one of the most important areas of drug research. Signalin... more Signal transduction therapy has become one of the most important areas of drug research. Signaling disorders represent a major cause for the pathological states and many of the recently identified validated target molecules of drug research are signal transduction related macromolecules, mostly kinases. Rational drug design is aimed to achieve the selective inhibition of distinct pathologically relevant signaling enzymes or
Current Medicinal Chemistry, 2008
Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistan... more Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.
ASSAY and Drug Development Technologies, 2005
Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies a... more Kinase inhibitors are at the forefront of modern drug research, where mostly three technologies are used for hit-and-lead finding: high throughput screening of random libraries, three-dimensional structure-based drug design based on X-ray data, and focused libraries around limited number of new cores. Our novel Nested Chemical Library (NCL) (Vichem Chemie Research Ltd., Budapest, Hungary) technology is based on a knowledge base approach, where focused libraries around selected cores are used to generate pharmacophore models. NCL was designed on the platform of a diverse kinase inhibitory library organized around 97 core structures. We have established a unique, proprietary kinase inhibitory chemistry around these core structures with small focused sublibraries around each core. All the compounds in our NCL library are stored in a big unified Structured Query Language database along with their measured and calculated physicochemical and ADME/toxicity (ADMET) properties, together with thousands of molecular descriptors calculated for each compound. Biochemical kinase inhibitory assays on selected, cloned kinase enzymes for a few hundred NCL compound sets can provide sufficient biological data for rational computerized design of new analogues, based on our pharmacophore model-generating 3DNET4W QSPAR (quantitative structure-property/activity relationships) approach. Using this pharmacophore modeling approach and the ADMET filters, we can preselect synthesizable compounds for hit-and-lead optimization. Starting from this point and integrating the information from QSPAR, high-quality leads can be generated within a small number of optimization cycles. Applying NCL technology we have developed lead compounds for several validated kinase targets.