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Annual reports in medicinal chemistry
Pharmaceutical research, Jan 11, 2015
The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ... more The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase ...
Journal of Molecular Graphics, 1993
information to draw on, therefore, it seems much more reliable to construct crude structural repr... more information to draw on, therefore, it seems much more reliable to construct crude structural representations of unknown membrane proteins using experimental observations rather than theoretical calculations as the basis. In the systems to be described, the results of protein chemistry, mutagenesis, and biophysical analysis are allied to the packing motif of bacteriorhodopsin to arrive at a crude appreciation of the structure of G-protein linked receptors. To this can be added the positions of positive charges across a very large alignment of sequences, the use of discriminator analysis and the concept of residue conservation, all of which help to refine the models produced. A similar approach can be used for proton channel of the vaculor H+-ATPase. In this case, the protein contains a very high helical content organized into 4 transmembrane segments. Medium resolution electron microscopy and image reconstruction revealed the molecular dimensions of the molecule, indicating that the complex was hexameric.
Journal of Medicinal Chemistry, 1992
The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium deri... more The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium derivatives and their substance P (SP) antagonist activity are described. All compounds were evaluated for their ability to displace SP from neurokinin-1 (NK-1) receptor sites using standard receptor binding methodology (rat forebrain membrane). 1,3-Diethyl-2-[3-(1,3-dihydro-1,3,3-timethyl-2H-indol-2-ylidene) -1-propenyl]-1H-naphth[2,3-d]imidazolium chloride (7a), a representative compound in this series, was further evaluated for SP antagonist activity in a guinea pig ileum contractility assay. In vivo SP antagonist activity of 7a was demonstrated using SP-induced salivation and paw edema models performed in rats.
![Research paper thumbnail of Imidazo[4,5-b]quinoxaline cyanines as neurokinin antagonists](https://attachments.academia-assets.com/44303874/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 1991
Bioorganic Medicinal Chemistry Letters, Mar 15, 2008
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic aci... more A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Annual reports in medicinal chemistry
Pharmaceutical research, Jan 11, 2015
The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ... more The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase ...
Journal of Molecular Graphics, 1993
information to draw on, therefore, it seems much more reliable to construct crude structural repr... more information to draw on, therefore, it seems much more reliable to construct crude structural representations of unknown membrane proteins using experimental observations rather than theoretical calculations as the basis. In the systems to be described, the results of protein chemistry, mutagenesis, and biophysical analysis are allied to the packing motif of bacteriorhodopsin to arrive at a crude appreciation of the structure of G-protein linked receptors. To this can be added the positions of positive charges across a very large alignment of sequences, the use of discriminator analysis and the concept of residue conservation, all of which help to refine the models produced. A similar approach can be used for proton channel of the vaculor H+-ATPase. In this case, the protein contains a very high helical content organized into 4 transmembrane segments. Medium resolution electron microscopy and image reconstruction revealed the molecular dimensions of the molecule, indicating that the complex was hexameric.
Journal of Medicinal Chemistry, 1992
The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium deri... more The synthesis of unsymmetrical naphth[2,3-d]imidazolium and bridged naphth[2,3-d]imidazolium derivatives and their substance P (SP) antagonist activity are described. All compounds were evaluated for their ability to displace SP from neurokinin-1 (NK-1) receptor sites using standard receptor binding methodology (rat forebrain membrane). 1,3-Diethyl-2-[3-(1,3-dihydro-1,3,3-timethyl-2H-indol-2-ylidene) -1-propenyl]-1H-naphth[2,3-d]imidazolium chloride (7a), a representative compound in this series, was further evaluated for SP antagonist activity in a guinea pig ileum contractility assay. In vivo SP antagonist activity of 7a was demonstrated using SP-induced salivation and paw edema models performed in rats.
Journal of Medicinal Chemistry, 1991
Bioorganic Medicinal Chemistry Letters, Mar 15, 2008
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic aci... more A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.