Lauren Dorosh - Academia.edu (original) (raw)

Papers by Lauren Dorosh

Research paper thumbnail of ffi cient and E ffi cacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinica... more The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the disco...

Research paper thumbnail of Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3Kδ-inhibitors in Respiratory Models of TH2 and TH1 Inflammation

Journal of Pharmacology and Experimental Therapeutics, 2019

We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship establis... more We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)d inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kd inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC 50 values for PI3Kd inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 mM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kd inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kd efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kd inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC 50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC 50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease.

Research paper thumbnail of The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious JAK1 Selective Inhibitor with Favorable Pharmacokinetic Properties

Journal of medicinal chemistry, Jan 20, 2017

The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is d... more The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.

Research paper thumbnail of Evaluation of JAK3 biology in autoimmune disease using a highly selective, irreversible JAK3 inhibitor

The Journal of pharmacology and experimental therapeutics, May 13, 2017

Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, e... more Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012). A selective JAK3 inhibitor may have a better therapeutic index, however, no compounds have been described that maintain JAK3 selectivity in cells, as well as against the kinome, with good physicochemical properties to test the JAK3 hypothesis in vivo. To quantify the biochemical basis for JAK isozyme selectivity, we determined that the apparent Km for each JAK isozyme ranged from 31.8 μM for JAK1 to 2.9 μM for JAK3. To confirm compound activity i...

Research paper thumbnail of P17-09. Immunization with a single HIV-1 envelope sequence can generate CD8+ T lymphocytes capable of recognizing multiple variant forms of envelope

Research paper thumbnail of Clonal Repertoires of Virus-Specific CD8+T Lymphocytes Are Shared in Mucosal and Systemic Compartments during Chronic Simian Immunodeficiency Virus Infection in Rhesus Monkeys

The Journal of Immunology, 2010

Immunodomination in the Evolution of Dominant Epitope-Speci c CD8 + T Lymphocyte Responses in Sim... more Immunodomination in the Evolution of Dominant Epitope-Speci c CD8 + T Lymphocyte Responses in Simian Immunode ciency Virus-Infected Rhesus Monkeys

Research paper thumbnail of ffi cient and E ffi cacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinica... more The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the disco...

Research paper thumbnail of Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3Kδ-inhibitors in Respiratory Models of TH2 and TH1 Inflammation

Journal of Pharmacology and Experimental Therapeutics, 2019

We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship establis... more We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)d inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kd inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC 50 values for PI3Kd inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 mM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kd inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kd efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kd inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC 50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC 50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease.

Research paper thumbnail of The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious JAK1 Selective Inhibitor with Favorable Pharmacokinetic Properties

Journal of medicinal chemistry, Jan 20, 2017

The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is d... more The discovery of a potent selective low dose JAK1 inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.

Research paper thumbnail of Evaluation of JAK3 biology in autoimmune disease using a highly selective, irreversible JAK3 inhibitor

The Journal of pharmacology and experimental therapeutics, May 13, 2017

Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, e... more Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012). A selective JAK3 inhibitor may have a better therapeutic index, however, no compounds have been described that maintain JAK3 selectivity in cells, as well as against the kinome, with good physicochemical properties to test the JAK3 hypothesis in vivo. To quantify the biochemical basis for JAK isozyme selectivity, we determined that the apparent Km for each JAK isozyme ranged from 31.8 μM for JAK1 to 2.9 μM for JAK3. To confirm compound activity i...

Research paper thumbnail of P17-09. Immunization with a single HIV-1 envelope sequence can generate CD8+ T lymphocytes capable of recognizing multiple variant forms of envelope

Research paper thumbnail of Clonal Repertoires of Virus-Specific CD8+T Lymphocytes Are Shared in Mucosal and Systemic Compartments during Chronic Simian Immunodeficiency Virus Infection in Rhesus Monkeys

The Journal of Immunology, 2010

Immunodomination in the Evolution of Dominant Epitope-Speci c CD8 + T Lymphocyte Responses in Sim... more Immunodomination in the Evolution of Dominant Epitope-Speci c CD8 + T Lymphocyte Responses in Simian Immunode ciency Virus-Infected Rhesus Monkeys