Helmut Mett - Academia.edu (original) (raw)
Papers by Helmut Mett
Eur J Clin Microbiol Infect D, 1987
The novel penem CGP 31 608 (5R, 6S, 8R) and its enantiomer CGP 32 879 (5S, 6R, 8S) were shown to ... more The novel penem CGP 31 608 (5R, 6S, 8R) and its enantiomer CGP 32 879 (5S, 6R, 8S) were shown to be essentially stable against hydrolysis by type Id fl-lactamase isolated from Pseudomonas aeruginosa 18S/H. CGP 31 608 was a potent progressive inhibitor of this enzyme 050 = 32/aM), which was only weakly inhibited by CGP 32 879 (I50 = 460/.aM). CGP 31 608 had the highest affinity for penicillin-binding protein (PBP) 4 from Escherichia colt K-12 (I50 = 1/ag/ml), followed by PBPs 2 (10/ag/ml) and 1A/1Bs (100 #g/ml); CGP 32 879 did not inhibit binding of laC-benzylpenieiUin to the PBPs. The steric configuration of the ~lactam nucleus of penems appears to strongly influence their affinity for fl-lactamases and target PBPs. The balanced spectrum of CGP 31 608 may be explained by its/3-1actamase stability and affinity for several vital PBPs.
Archiv Der Pharmazie, 1996
... 371 Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors ... more ... 371 Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC) Jiirg Zimmermann*, Giorgio Caravatti, Helmut Mett, Thomas Meyer, Marcel Miiller, Nicholas B.Lydon, and Doriano Fabbro ...
![Research paper thumbnail of [(Alkylamino)methyl]acrylophenones: potent and selective inhibitors of the epidermal growth factor receptor protein tyrosine kinase](https://attachments.academia-assets.com/48327486/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, Jul 1, 1995
Alkylamino)methyllacrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as ... more Alkylamino)methyllacrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as the benzyloxy or (benzoylsulfony1)oxy group in the 4-position, represent a novel class of inhibitors of the epidermal growth factor (EGF) receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serineithreonine kinases. The-most active compounds inhibited the EGF receptor protein tyrosine kinase from A431 cell membranes with IC50 values of c0.5 pM. Derivatives with a benzyloxy substituent in the 4-position of the aromatic ring inhibited both the EGF receptor kinase and the proliferation of a n EGF-dependent mouse epidermal keratinocyte cell line (BALBNK) but were only marginally active in the inhibition of the cellular EGF-dependent tyrosine phosphorylation. Compound 18 inhibited ligand-induced tyrosine phosphorylation and BALBMK cell proliferation with IC50 values of approximately 100 and 1.21 pM, respectively, and showed antitumor activity in vivo in a nude mouse model. However, the discrepancy between the IC50 values for antiproliferative activity and cellular tyrosine phosphorylation as well as the relatively low tolerability in animals suggests a second site of action of this class of inhibitors. Nevertheless, [(alkylamino)methyllacrylophenones and (alky1amino)propiophenones may prove to be interesting tools for studying the action of tyrosine kinases. 0 1995 American Chemical Society
J Antimicrob Chemother, 1988
When ultrasonic disintegration of bacteria was employed to liberate intracellular beta-lactamases... more When ultrasonic disintegration of bacteria was employed to liberate intracellular beta-lactamases there was rapid and irreversible inactivation of the type-Id beta-lactamase from Pseudomonas aeruginosa. Various type-V beta-lactamases (PSE-2, 3 and 4) from P. aeruginosa, as well as Enterobacter cloacae type-Ia beta-lactamase were much less affected by sonication. None of the beta-lactamases was inactivated by French Press disruption. We suggest that French Press disruption should be the method of choice for the release of beta-lactamases, unless the enzyme in question is known to be unaffected by ultrasonic treatment.
Int J Cancer, 1999
A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal gr... more A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo. Int. J. Cancer, 76, 154-163 (1998) have been repeated and re-evaluated. We regret to inform you that the in vivo data could not be reproduced and therefore retract these data. All in vitro and cellular data remain valid.
Journal of Antibiotics, Mar 25, 1995
Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine... more Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine kinase from the culture broth of the fungus Paecilomyces carneus P-177. The novel anthraquinones inhibit epidermal growth factor receptor protein tyrosine kinase in the micromolar range. Two compounds, paeciloquinones A and C, are potent and selective inhibitors of the v-abl protein tyrosine kinase with an IC50 of 0.4 microM. Dependent on the fermentation conditions, partially different sets of paeciloquinones may be produced. An HPLC method allows separation of all major active components.
Cancer Research, 1996
Oncogenic activation of AbI proteins due to structural modifications can occur as a result of vir... more Oncogenic activation of AbI proteins due to structural modifications can occur as a result of viral transduction or chromosomal translocation. The tyrosine protein kinase activity ofoncogenic AbI proteins Is known to be essential for their transforming activity. Therefore, we have attempted to identify selective inhibitors of the AbI tyrosine protein kinase. Herein we describean inhibiter (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phe nylaminopyrimidine class, which is highly active in vitro and in vivo. Submicromolar concentrations of the compound inhibited both v-Abl and PDGF receptor autophosphorylation and PDGF-induced c-fos mRNA expression selectively in Intact cells. In contrast, ligand-Induced growth factor receptor autophosphorylation in response to epidermat growth factor (EGF), Insulin-like growth factor-I, and insulin showed no or weak inhibition by high concentrations of CGP 57148. c-fos mRNA expression induced by EGF, fibroblastgrowth factor, or phorbolester was also insensitive to inhibition by CGP 57148. In antiproliferative assays, the compound was more than 30-i®-fold more potent in inhibiting growth of v-aM-transformed PB-3c cells and v-sis-transformed BALBIC 3T3 cells relative to inhibition of EGF-dependent BALB/MK cells, interleukin-3dependent FDC-P1 cells, and the T24 bladder carcinoma line. Further more, anchorage-independent growth of v-abE-and v-sis-transformed
Cheminform, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Int J Cancer, 1998
A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal gr... more A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo. Int. J. Cancer, 76, 154-163 (1998) have been repeated and re-evaluated. We regret to inform you that the in vivo data could not be reproduced and therefore retract these data. All in vitro and cellular data remain valid.
A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Th... more A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC50 values in the low nanomolar range. A few of them however, notably protein kinases CK1 and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC50 values in the micromolar range. With all protein kinases tested, namely PKA, CK1, CK2, MAP kinase (ERK-1), c-Fgr, Lyn, CSK and TPK-IIB/p38Syk, staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Val66, Phe113 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10- 100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp. It can be concluded from these data that the catalytic sites of protein kinases are divergent enough as to allow a competitive inhibitor like staurosporine to be fairly selective, a feature that can be enhanced by suitable modifications designed based on the structure of the catalytic site of the kinase.
A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Th... more A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC,,, values in the low nanomolar range. A few of them however, notably protein kinases CKI and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC,,, values in the micromolar range. With all protein kinases tested. namely PKA, CKI, CK2, MAP kinase (ERK-I), c-Fgr, Lyn, CSK and TPK-IIB/p38.'", staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Va166, P h e l l 3 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10-100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp.
Journal of Medicinal Chemistry, Jul 1, 1996
Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of th... more Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines have been identified as a novel class of potent EGF-R protein tyrosine kinase inhibitors. In an interactive process, this class of compounds was then optimized. 13, 14, 28, 36, 37, and 44, the most potent compounds of this series, inhibited the EGF-R PTK with IC50 values in the low nanomolar range. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 36, 37, and 44 at IC50 values between 0.1 and 0.4 microM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM. In addition, these compounds were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with IC50 values between 0.1 and 2 microM, but did not affect c-fos mRNA induction in response to PDGF or PMA (IC50 >100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. From SAR studies, a binding mode for 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines as well as for the structurally related 4-(phenylamino)quinazolines at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)7H-pyrrolo[2,3-d]pyrimidines therefore represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.
We have studied the action of various antimicrobial agents in microbiological media and in human ... more We have studied the action of various antimicrobial agents in microbiological media and in human duodenopancreatic secretions. In the latter medium, clioquinol exhibited a rapid bactericidal effect on both growing and stationary bacteria at concentrations near its MIC. However, it was merely bacteriostatic in microbiological media, even at high concentrations. Phanquinone, chlorquinaldol, and, to a lesser extent, also chloramphenicol and trimethoprim likewise displayed enhanced bactericidal activity in duodeno-pancreatic secretions, but various other antibacterial agents did not. These findings suggest that duodeno-pancreatic secretions contain a factor augmenting the antibacterial activity of a number of drugs.
Eur J Clin Microbiol Infect D, 1987
The novel penem CGP 31 608 (5R, 6S, 8R) and its enantiomer CGP 32 879 (5S, 6R, 8S) were shown to ... more The novel penem CGP 31 608 (5R, 6S, 8R) and its enantiomer CGP 32 879 (5S, 6R, 8S) were shown to be essentially stable against hydrolysis by type Id fl-lactamase isolated from Pseudomonas aeruginosa 18S/H. CGP 31 608 was a potent progressive inhibitor of this enzyme 050 = 32/aM), which was only weakly inhibited by CGP 32 879 (I50 = 460/.aM). CGP 31 608 had the highest affinity for penicillin-binding protein (PBP) 4 from Escherichia colt K-12 (I50 = 1/ag/ml), followed by PBPs 2 (10/ag/ml) and 1A/1Bs (100 #g/ml); CGP 32 879 did not inhibit binding of laC-benzylpenieiUin to the PBPs. The steric configuration of the ~lactam nucleus of penems appears to strongly influence their affinity for fl-lactamases and target PBPs. The balanced spectrum of CGP 31 608 may be explained by its/3-1actamase stability and affinity for several vital PBPs.
Archiv Der Pharmazie, 1996
... 371 Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors ... more ... 371 Phenylamino-Pyrimidine (PAP) Derivatives: A New Class of Potent and Selective Inhibitors of Protein Kinase C (PKC) Jiirg Zimmermann*, Giorgio Caravatti, Helmut Mett, Thomas Meyer, Marcel Miiller, Nicholas B.Lydon, and Doriano Fabbro ...
Journal of Medicinal Chemistry, Jul 1, 1995
Alkylamino)methyllacrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as ... more Alkylamino)methyllacrylophenones and (alkylamino)propiophenones, bearing a spacer moiety such as the benzyloxy or (benzoylsulfony1)oxy group in the 4-position, represent a novel class of inhibitors of the epidermal growth factor (EGF) receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serineithreonine kinases. The-most active compounds inhibited the EGF receptor protein tyrosine kinase from A431 cell membranes with IC50 values of c0.5 pM. Derivatives with a benzyloxy substituent in the 4-position of the aromatic ring inhibited both the EGF receptor kinase and the proliferation of a n EGF-dependent mouse epidermal keratinocyte cell line (BALBNK) but were only marginally active in the inhibition of the cellular EGF-dependent tyrosine phosphorylation. Compound 18 inhibited ligand-induced tyrosine phosphorylation and BALBMK cell proliferation with IC50 values of approximately 100 and 1.21 pM, respectively, and showed antitumor activity in vivo in a nude mouse model. However, the discrepancy between the IC50 values for antiproliferative activity and cellular tyrosine phosphorylation as well as the relatively low tolerability in animals suggests a second site of action of this class of inhibitors. Nevertheless, [(alkylamino)methyllacrylophenones and (alky1amino)propiophenones may prove to be interesting tools for studying the action of tyrosine kinases. 0 1995 American Chemical Society
J Antimicrob Chemother, 1988
When ultrasonic disintegration of bacteria was employed to liberate intracellular beta-lactamases... more When ultrasonic disintegration of bacteria was employed to liberate intracellular beta-lactamases there was rapid and irreversible inactivation of the type-Id beta-lactamase from Pseudomonas aeruginosa. Various type-V beta-lactamases (PSE-2, 3 and 4) from P. aeruginosa, as well as Enterobacter cloacae type-Ia beta-lactamase were much less affected by sonication. None of the beta-lactamases was inactivated by French Press disruption. We suggest that French Press disruption should be the method of choice for the release of beta-lactamases, unless the enzyme in question is known to be unaffected by ultrasonic treatment.
Int J Cancer, 1999
A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal gr... more A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo. Int. J. Cancer, 76, 154-163 (1998) have been repeated and re-evaluated. We regret to inform you that the in vivo data could not be reproduced and therefore retract these data. All in vitro and cellular data remain valid.
Journal of Antibiotics, Mar 25, 1995
Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine... more Paeciloquinones A to F as well as versiconol have been isolated as inhibitors of protein tyrosine kinase from the culture broth of the fungus Paecilomyces carneus P-177. The novel anthraquinones inhibit epidermal growth factor receptor protein tyrosine kinase in the micromolar range. Two compounds, paeciloquinones A and C, are potent and selective inhibitors of the v-abl protein tyrosine kinase with an IC50 of 0.4 microM. Dependent on the fermentation conditions, partially different sets of paeciloquinones may be produced. An HPLC method allows separation of all major active components.
Cancer Research, 1996
Oncogenic activation of AbI proteins due to structural modifications can occur as a result of vir... more Oncogenic activation of AbI proteins due to structural modifications can occur as a result of viral transduction or chromosomal translocation. The tyrosine protein kinase activity ofoncogenic AbI proteins Is known to be essential for their transforming activity. Therefore, we have attempted to identify selective inhibitors of the AbI tyrosine protein kinase. Herein we describean inhibiter (CGP 57148) of the Abl and platelet-derived growth factor (PDGF) receptor protein-tyrosine kinases from the 2-phe nylaminopyrimidine class, which is highly active in vitro and in vivo. Submicromolar concentrations of the compound inhibited both v-Abl and PDGF receptor autophosphorylation and PDGF-induced c-fos mRNA expression selectively in Intact cells. In contrast, ligand-Induced growth factor receptor autophosphorylation in response to epidermat growth factor (EGF), Insulin-like growth factor-I, and insulin showed no or weak inhibition by high concentrations of CGP 57148. c-fos mRNA expression induced by EGF, fibroblastgrowth factor, or phorbolester was also insensitive to inhibition by CGP 57148. In antiproliferative assays, the compound was more than 30-i®-fold more potent in inhibiting growth of v-aM-transformed PB-3c cells and v-sis-transformed BALBIC 3T3 cells relative to inhibition of EGF-dependent BALB/MK cells, interleukin-3dependent FDC-P1 cells, and the T24 bladder carcinoma line. Further more, anchorage-independent growth of v-abE-and v-sis-transformed
Cheminform, 2010
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Int J Cancer, 1998
A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal gr... more A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo. Int. J. Cancer, 76, 154-163 (1998) have been repeated and re-evaluated. We regret to inform you that the in vivo data could not be reproduced and therefore retract these data. All in vitro and cellular data remain valid.
A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Th... more A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC50 values in the low nanomolar range. A few of them however, notably protein kinases CK1 and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC50 values in the micromolar range. With all protein kinases tested, namely PKA, CK1, CK2, MAP kinase (ERK-1), c-Fgr, Lyn, CSK and TPK-IIB/p38Syk, staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Val66, Phe113 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10- 100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp. It can be concluded from these data that the catalytic sites of protein kinases are divergent enough as to allow a competitive inhibitor like staurosporine to be fairly selective, a feature that can be enhanced by suitable modifications designed based on the structure of the catalytic site of the kinase.
A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Th... more A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC,,, values in the low nanomolar range. A few of them however, notably protein kinases CKI and CK2, mitogen-activated protein (MAP) kinase and protein-tyrosine kinase CSK, are relatively refractory to staurosporine inhibition, exhibiting IC,,, values in the micromolar range. With all protein kinases tested. namely PKA, CKI, CK2, MAP kinase (ERK-I), c-Fgr, Lyn, CSK and TPK-IIB/p38.'", staurosporine inhibition was competitive with respect to ATP, regardless of its inhibitory power. In contrast, either uncompetitive or noncompetitive kinetics of inhibition with respect to the phosphoacceptor substrate were exhibited by Ser/Thr and Tyr-specific protein kinases, respectively, consistent with a different mechanism of catalysis by these two sub-families of kinases. Computer modeling based on PKA crystal structure in conjunction with sequence analysis suggest that the low sensitivity to staurosporine of CK2 may be accounted for by the bulky nature of three residues, Va166, P h e l l 3 and Ile174 which are homologous to PKA Ala70, Met120 and Thr183, respectively. In contrast these PKA residues are either conserved or replaced by smaller ones in protein kinases highly sensitive to staurosporine inhibition. On the other hand, His160 which is homologous to PKA Glu170, appears to be responsible for the unique behaviour of CK2 with respect to a staurosporine derivative (CGP44171A) bearing a negatively charged benzoyl substituent: while CGP44171A is 10-100-fold less effective than staurosporine against PKA and most of the other protein kinases tested, it is actually more effective than staurosporine for CK2 inhibition, but it looses part of its efficacy if it is tested on a CK2 mutant (H160D) in which His160 has been replaced by Asp.
Journal of Medicinal Chemistry, Jul 1, 1996
Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of th... more Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGF-R protein tyrosine kinase (PTK), 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines have been identified as a novel class of potent EGF-R protein tyrosine kinase inhibitors. In an interactive process, this class of compounds was then optimized. 13, 14, 28, 36, 37, and 44, the most potent compounds of this series, inhibited the EGF-R PTK with IC50 values in the low nanomolar range. High selectivity toward a panel of nonreceptor tyrosine kinases (c-Src, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by compounds 13, 36, 37, and 44 at IC50 values between 0.1 and 0.4 microM, whereas PDGF-induced tyrosine phosphorylation was not affected by concentrations up to 10 microM. In addition, these compounds were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with IC50 values between 0.1 and 2 microM, but did not affect c-fos mRNA induction in response to PDGF or PMA (IC50 >100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. From SAR studies, a binding mode for 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines as well as for the structurally related 4-(phenylamino)quinazolines at the ATP-binding site of the EGF-R tyrosine kinase is proposed. 4-(Phenylamino)7H-pyrrolo[2,3-d]pyrimidines therefore represent a new class of highly potent tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the potential for further evaluation as anticancer agents.
We have studied the action of various antimicrobial agents in microbiological media and in human ... more We have studied the action of various antimicrobial agents in microbiological media and in human duodenopancreatic secretions. In the latter medium, clioquinol exhibited a rapid bactericidal effect on both growing and stationary bacteria at concentrations near its MIC. However, it was merely bacteriostatic in microbiological media, even at high concentrations. Phanquinone, chlorquinaldol, and, to a lesser extent, also chloramphenicol and trimethoprim likewise displayed enhanced bactericidal activity in duodeno-pancreatic secretions, but various other antibacterial agents did not. These findings suggest that duodeno-pancreatic secretions contain a factor augmenting the antibacterial activity of a number of drugs.