Cathy Bull - Academia.edu (original) (raw)
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University of Maryland School of Medicine
Beckman Research Institute of City of Hope
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Papers by Cathy Bull
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2009
Molecular Cancer Therapeutics, 2011
Intervirology, 1992
Recurrence rates of genital infections are significantly higher for herpes simplex virus (HSV) ty... more Recurrence rates of genital infections are significantly higher for herpes simplex virus (HSV) type 2 than HSV type 1. Reasons for this difference are not known. In this report, multiple strains of HSV-1 and HSV-2 were evaluated in the guinea-pig model. HSV-2 strains showed significantly higher genital lesion recurrence than HSV-1, including HSV-1 McKrae strain which is highly recurrent in ocular infections. HSV-2 strains were also associated with more frequent asymptomatic vaginal virus shedding. Further study showed that HSV-1 strains replicated as well as HSV-2 in both the genital tract and the nervous system during acute infection. In addition, no difference was detected between HSV-1 and HSV-2 in nervous system latency. Thus, a number of possible explanations for the observed difference in genital herpes recurrence rates were examined and excluded.
ChemMedChem, Jan 16, 2016
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, incl... more The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a ...
Journal of Medicinal Chemistry, 2016
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-y... more The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The co-crystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2 and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
American Journal of Clinical Pathology, 2012
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2013
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) ... more Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with subnanomolar IC 50 s against PI3Ka and PI3Kd. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Ka compared with PI3Kb in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. Mol Cancer Ther; 12(11); 2319-30. Ó2013 AACR.
Molecular Cancer Therapeutics, 2011
Molecular Cancer Therapeutics, 2009
![Research paper thumbnail of Discovery and Optimization of a Series of 3-(3-Phenyl-3 H -imidazo[4,5- b ]pyridin-2-yl)pyridin-2-amines: Orally Bioavailable, Selective, and Potent ATP-Independent Akt Inhibitors](https://attachments.academia-assets.com/50748208/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2012
This paper describes the implementation of a biochemical and biophysical screening strategy to id... more This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2009
Molecular Cancer Therapeutics, 2011
Intervirology, 1992
Recurrence rates of genital infections are significantly higher for herpes simplex virus (HSV) ty... more Recurrence rates of genital infections are significantly higher for herpes simplex virus (HSV) type 2 than HSV type 1. Reasons for this difference are not known. In this report, multiple strains of HSV-1 and HSV-2 were evaluated in the guinea-pig model. HSV-2 strains showed significantly higher genital lesion recurrence than HSV-1, including HSV-1 McKrae strain which is highly recurrent in ocular infections. HSV-2 strains were also associated with more frequent asymptomatic vaginal virus shedding. Further study showed that HSV-1 strains replicated as well as HSV-2 in both the genital tract and the nervous system during acute infection. In addition, no difference was detected between HSV-1 and HSV-2 in nervous system latency. Thus, a number of possible explanations for the observed difference in genital herpes recurrence rates were examined and excluded.
ChemMedChem, Jan 16, 2016
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, incl... more The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a ...
Journal of Medicinal Chemistry, 2016
The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-y... more The work in this paper describes the optimization of the 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (21a). The co-crystal structure of compound 21a bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic potency against AKT1, AKT2 and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound 21a also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
American Journal of Clinical Pathology, 2012
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2013
Molecular Cancer Therapeutics, 2013
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) ... more Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with subnanomolar IC 50 s against PI3Ka and PI3Kd. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Ka compared with PI3Kb in cells. BAY 80-6946 showed superior antitumor activity (>40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non-small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. Mol Cancer Ther; 12(11); 2319-30. Ó2013 AACR.
Molecular Cancer Therapeutics, 2011
Molecular Cancer Therapeutics, 2009
Journal of Medicinal Chemistry, 2012
This paper describes the implementation of a biochemical and biophysical screening strategy to id... more This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.