An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
L'invention concerne de nouvelles pyrido [2,3-b] pyrazinones de formule (I) et (II) ou des se... more L'invention concerne de nouvelles pyrido [2,3-b] pyrazinones de formule (I) et (II) ou des sels pharmaceutiquement acceptables de celles-ci. L'invention concerne egalement des compositions pharmaceutiques et l'utilisation des composes pour traiter des maladies ou des troubles qui sont dependants de bromodomaines de la famille BET, par exemple le cancer. La presente invention concerne en outre des methodes de preparation et d'utilisation de ces composes.
La presente invention concerne des composes de formule I, dans laquelle A, B, D, E et F sont tels... more La presente invention concerne des composes de formule I, dans laquelle A, B, D, E et F sont tels que definis dans la description. Ces composes s'utilisent dans le traitement de maladies, troubles et pathologies associes au systeme nerveux central (SNC), tels que notamment pas pas exclusivement la dependance a la nicotine, la schizophrenie, la depression, la maladie d'Alzheimer, la maladie de Parkinson et le THADA. Cette invention concerne egalement des compositions pharmaceutiques contenant lesdits composes ainsi que des methodes de traitement fondees sur l'utilisation de ces composes.
L'invention concerne des compositions pharmaceutiques pour le traitement de la dependance ou ... more L'invention concerne des compositions pharmaceutiques pour le traitement de la dependance ou de l'accoutumance a l'alcool ou a la cocaine, au tabac, la reduction des symptomes du sevrage alcoolique ou bien l'aide a l'arret ou a la diminution de la consommation d'alcool ou de l'usage de substances toxiques ou encore d'autres dependances comportementales, notamment le jeu. Ces compositions pharmaceutiques sont constituees d'une association therapeutiquement efficace d'un antagoniste du recepteur opioide, d'un antagoniste du recepteur CB-1 et d'un excipient pharmaceutiquement acceptable. L'invention concerne egalement une methode d'utilisation de ces composes .
Proceedings of the National Academy of Sciences of the United States of America, Jul 31, 2018
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneous... more Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to me...
European journal of medicinal chemistry, Jan 10, 2018
Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) a... more Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar p...
Chemical probes are required for preclinical target validation to interrogate novel biological ta... more Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB Binding Protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization, that paid particular attention to physiochemical properties, delivered chemical probes with desirable potency, selectivity and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in severa... more Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past two decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of PF-06651600 (11), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this specific JAK3 inhibitor 11...
By use of a structure-based computational method for identification of structurally novel Janus k... more By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
L'invention concerne de nouvelles pyrido [2,3-b] pyrazinones de formule (I) et (II) ou des se... more L'invention concerne de nouvelles pyrido [2,3-b] pyrazinones de formule (I) et (II) ou des sels pharmaceutiquement acceptables de celles-ci. L'invention concerne egalement des compositions pharmaceutiques et l'utilisation des composes pour traiter des maladies ou des troubles qui sont dependants de bromodomaines de la famille BET, par exemple le cancer. La presente invention concerne en outre des methodes de preparation et d'utilisation de ces composes.
La presente invention concerne des composes de formule I, dans laquelle A, B, D, E et F sont tels... more La presente invention concerne des composes de formule I, dans laquelle A, B, D, E et F sont tels que definis dans la description. Ces composes s'utilisent dans le traitement de maladies, troubles et pathologies associes au systeme nerveux central (SNC), tels que notamment pas pas exclusivement la dependance a la nicotine, la schizophrenie, la depression, la maladie d'Alzheimer, la maladie de Parkinson et le THADA. Cette invention concerne egalement des compositions pharmaceutiques contenant lesdits composes ainsi que des methodes de traitement fondees sur l'utilisation de ces composes.
L'invention concerne des compositions pharmaceutiques pour le traitement de la dependance ou ... more L'invention concerne des compositions pharmaceutiques pour le traitement de la dependance ou de l'accoutumance a l'alcool ou a la cocaine, au tabac, la reduction des symptomes du sevrage alcoolique ou bien l'aide a l'arret ou a la diminution de la consommation d'alcool ou de l'usage de substances toxiques ou encore d'autres dependances comportementales, notamment le jeu. Ces compositions pharmaceutiques sont constituees d'une association therapeutiquement efficace d'un antagoniste du recepteur opioide, d'un antagoniste du recepteur CB-1 et d'un excipient pharmaceutiquement acceptable. L'invention concerne egalement une methode d'utilisation de ces composes .
Proceedings of the National Academy of Sciences of the United States of America, Jul 31, 2018
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneous... more Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to me...
European journal of medicinal chemistry, Jan 10, 2018
Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) a... more Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar p...
Chemical probes are required for preclinical target validation to interrogate novel biological ta... more Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB Binding Protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization, that paid particular attention to physiochemical properties, delivered chemical probes with desirable potency, selectivity and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in severa... more Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past two decades, identification of highly selective JAK3 inhibitors has eluded the scientific community. A significant effort within our research organization has resulted in the identification of the first orally active JAK3 specific inhibitor, which achieves JAK isoform specificity through covalent interaction with a unique JAK3 residue Cys-909. The relatively rapid resynthesis rate of the JAK3 enzyme presented a unique challenge in the design of covalent inhibitors with appropriate pharmacodynamics properties coupled with limited unwanted off-target reactivity. This effort resulted in the identification of PF-06651600 (11), a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this specific JAK3 inhibitor 11...
By use of a structure-based computational method for identification of structurally novel Janus k... more By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
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Papers by Jotham Coe