Yingqing Ran - Academia.edu (original) (raw)
Papers by Yingqing Ran
Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially ta... more Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially targeted long-circulating liposomes, provide the possibility of delivering drugs specifically to targeted cancer tissues, thus increasing anticancer activity and minimizing toxicity. 2-4'-Amino-3'-methylphenylbenzothiazole (AMPB), a potent anticancer drug, is inappropriate for traditional oral or parenteral formulations because of its severe dose-limiting hepatotoxicity. Several PEG-coated liposomal formulations were developed by using different drug/lipid ratios. Particle size and encapsulation efficiency of each formulation were investigated; the most stable liposomal formulation was selected for animal testing. The formulation with AMPB/egg phosphatidyl choline/cholesterol/1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000, PEG2000-DSPE in a 1/5/5/1 molar ratio is the best formulation. This formulation contains 2 mg/ml AMPB with encapsulation efficiency above 95%, average particle size 120-150 nm. Daunorubicin is a well known anti cancer agent. To minimize its cardiotoxicity, targeted folate-PEG-liposomes were developed in this study. The pH-gradient loading method was used to increase the drug loading efficiency. Above 97% loading efficiency was reached by creating a 3 to 4 unit pH difference across the liposome membrane. The final folate-PEG-liposomml formulation contained 2.5 mg/ml daunorubicin HCI, with average particle size of 110∼120 nm, pH of ∼7.4, and a drug/lipid ratio 1/20 (w/w). The solvent, chloroform, commonly used for liposome preparation, is harmful to humans. Therefore, halothane, a commonly used inhalation anesthetic, was used in this study in place of chloroform to prepare liposomes. AMPB and several other proprietary anticancer agents were formulated in liposomes by using halothane and chloroform. No obvious differences in physicochemical properties were observed between halothane and chloroform mediated liposomes
Asian Journal of Applied Sciences, 2016
Several commonly used particle size reduction techniques were evaluated in this study. Two excip... more Several commonly used particle size reduction techniques were evaluated in this study. Two excipients Avicel PH 101, calcium phosphate dihydrate and a poorly soluble compound naproxen were used for evaluation. All the techniques tested in this study: tissue grinder, glass beads, Glen Mills high speed mixer, polytron and sonication showed different degree of particle size reduction. The polytron in combination with the sonicator proved to be the most suitable technique for particle size reduction in discovery with limited API available. The processed particle sizes from the polytron technique were comparable to the glass tissue grinders while minimizing the loss of sample. Glass beads created small particle sizes (under 20 microns) depending on the length of time, but it was overly time consuming. Glen-mill needs about hundreds of milligram material to work with despite the comparable particle size reduction.
The AAPS Journal, 2013
Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical indust... more Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated.
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet ... more Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
ACS Medicinal Chemistry Letters, 2011
Journal of Medicinal Chemistry, 2007
Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conf... more Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC 50 of 30) 0.009 µM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC 50 of 30) 0.03 µM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
Journal of Medicinal Chemistry, 2006
We report on the discovery of benzo-and pyridino-thiazolothiopurines as potent heat shock protein... more We report on the discovery of benzo-and pyridino-thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7′-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H-purin-6-ylamine).
AAPS PharmSciTech, 2003
The first step in the preparation of liposomes is to dissolve the lipids into organic solvent. Th... more The first step in the preparation of liposomes is to dissolve the lipids into organic solvent. The solvent must be volatile and have high solubility for lipids. This requirement has introduced safety issues. Chloroform and ether are the commonly used solvents. Chloroform was used as an anesthetic during surgery for many years before its harmful effects on the liver and kidney were recognized. Based on animal studies, the Department of Health and Human Services (DHHS), the International Agency for Research on Cancer (IARC), and the Environmental Protection Agency (EPA) have determined that chloroform is possibly carcinogenic to humans. The breakdown products of chloroform in air include hydrogen chloride and phosgene, which are even more toxic than chloroform. Ether, while relatively nontoxic, is highly flammable. Both of these agents have been abandoned as anesthetics for clinical use. Even though only a small amount of residue would exist in liposomal formulations, it is still not acceptable. Because chloroform and ether evaporate very quickly, they would be harmful to the lab workers who were exposed to them. Chloroform is also toxic to aquatic and soil organisms after entering the natural environment, which is a probable consequence of using it as a solvent. 7,8,9
ACS Medicinal Chemistry Letters
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer... more Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
ACS Medicinal Chemistry Letters
Bioorganic & Medicinal Chemistry Letters
Journal of pharmaceutical sciences, Jan 5, 2017
The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and p... more The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and physicochemical properties. Among the physicochemical properties, solubility and dissolution rate often are the most critical factors affecting the oral bioavailability of a compound. The increasing challenge for the pharmaceutical industry is to achieve reasonable oral bioavailability of poorly water-soluble drug candidates. G-F is a potent and selective B-Raf (rapidly accelerated fibrosarcoma) inhibitor with poor water solubility and moderate permeability, which resulted in an absorption-limited exposure in preclinical safety studies. The intrinsic solubility of G-F is 8 μg/mL (i.e., 0.0188 nM). In this study, pH adjustment combined with cosolvency, micellization, or complexation was applied as a technique to enhance the solubility of G-F. pH 9.5 and 4 buffers were selected to combine with the solubilization agents based on G-F's acidic pKa of 7.47. The solubilization power of each ...
Toxicology and applied pharmacology, Jan 13, 2017
Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdraw... more Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone. The purpose of the current study is to determine if serum profiling of 19 individual bile acids by liquid chromatography-mass spectrometry (LC/MS) can detect perturbations in bile acid homeostasis in rats after acute intravenous (IV) administration of vehicle or 5, 25, or 50mg/kg troglitazone. Minimal serum transaminase elevations (approximately two-fold) were observed with no evidence of microscopic liv...
Journal of medicinal chemistry, Jan 11, 2017
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interest... more Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781; TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM, BRD4(1) IC50 = 5,100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays anti-tumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a...
Bioorganic & medicinal chemistry letters, Jul 1, 2017
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged sc... more A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.
Journal of pharmaceutical and biomedical analysis, Jan 18, 2017
Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently use... more Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently used for drug delivery and administration. The compatibility of a parenteral drug microdose formulation in intravenous infusion (IV) devices was studied to support the clinical determination of absolute bioavailability by the microdosing method. The investigational microdose formulation containing PEG was found prone to significant loss of potency within hours of storage in the PVC IV tubing due to degradation. Degradation occurred only when both PEG and PVC tubing were present. The degradation product could not be detected by LC/MS due to the significant interference from the high concentration of PEG (4%) matrix and the extremely low level of drug (0.6ppm). To obtain structural information of the degradation impurity and understand the cause of the degradation, a simple heart-cutting 2D-LC/MS approach was utilized to effectively separate the impurity from the complex PEG oligomers and ove...
Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially ta... more Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially targeted long-circulating liposomes, provide the possibility of delivering drugs specifically to targeted cancer tissues, thus increasing anticancer activity and minimizing toxicity. 2-4'-Amino-3'-methylphenylbenzothiazole (AMPB), a potent anticancer drug, is inappropriate for traditional oral or parenteral formulations because of its severe dose-limiting hepatotoxicity. Several PEG-coated liposomal formulations were developed by using different drug/lipid ratios. Particle size and encapsulation efficiency of each formulation were investigated; the most stable liposomal formulation was selected for animal testing. The formulation with AMPB/egg phosphatidyl choline/cholesterol/1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000, PEG2000-DSPE in a 1/5/5/1 molar ratio is the best formulation. This formulation contains 2 mg/ml AMPB with encapsulation efficiency above 95%, average particle size 120-150 nm. Daunorubicin is a well known anti cancer agent. To minimize its cardiotoxicity, targeted folate-PEG-liposomes were developed in this study. The pH-gradient loading method was used to increase the drug loading efficiency. Above 97% loading efficiency was reached by creating a 3 to 4 unit pH difference across the liposome membrane. The final folate-PEG-liposomml formulation contained 2.5 mg/ml daunorubicin HCI, with average particle size of 110∼120 nm, pH of ∼7.4, and a drug/lipid ratio 1/20 (w/w). The solvent, chloroform, commonly used for liposome preparation, is harmful to humans. Therefore, halothane, a commonly used inhalation anesthetic, was used in this study in place of chloroform to prepare liposomes. AMPB and several other proprietary anticancer agents were formulated in liposomes by using halothane and chloroform. No obvious differences in physicochemical properties were observed between halothane and chloroform mediated liposomes
Asian Journal of Applied Sciences, 2016
Several commonly used particle size reduction techniques were evaluated in this study. Two excip... more Several commonly used particle size reduction techniques were evaluated in this study. Two excipients Avicel PH 101, calcium phosphate dihydrate and a poorly soluble compound naproxen were used for evaluation. All the techniques tested in this study: tissue grinder, glass beads, Glen Mills high speed mixer, polytron and sonication showed different degree of particle size reduction. The polytron in combination with the sonicator proved to be the most suitable technique for particle size reduction in discovery with limited API available. The processed particle sizes from the polytron technique were comparable to the glass tissue grinders while minimizing the loss of sample. Glass beads created small particle sizes (under 20 microns) depending on the length of time, but it was overly time consuming. Glen-mill needs about hundreds of milligram material to work with despite the comparable particle size reduction.
The AAPS Journal, 2013
Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical indust... more Drug polymer-based amorphous solid dispersions (ASD) are widely used in the pharmaceutical industry to improve bioavailability for poorly water-soluble compounds. Spray-drying is the most common process involved in the manufacturing of ASD material. However, spray-drying involves a high investment of material quantity and time. Lower investment manufacturing processes such as fast evaporation and freeze-drying (lyophilization) have been developed to manufacture ASD at the bench level. The general belief is that the overall performance of ASD material is thermodynamically driven and should be independent of the manufacturing process. However, no formal comparison has been made to assess the in vivo performance of material generated by different processes. This study compares the in vitro and in vivo properties of ASD material generated by fast evaporation, lyophilization, and spray-drying methods using griseofulvin as a model compound and hydroxypropyl methylcellulose acetate succinate as the polymer matrix. Our data suggest that despite minor differences in the formulation release properties and stability of the ASD materials, the overall exposure is comparable between the three manufacturing processes under the conditions examined. These results suggest that fast evaporation and lyophilization may be suitable to generate ASD material for oral evaluation. However, caution should be exercised since the general applicability of the present findings will need to be further evaluated.
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet ... more Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
ACS Medicinal Chemistry Letters, 2011
Journal of Medicinal Chemistry, 2007
Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conf... more Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC 50 of 30) 0.009 µM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC 50 of 30) 0.03 µM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
Journal of Medicinal Chemistry, 2006
We report on the discovery of benzo-and pyridino-thiazolothiopurines as potent heat shock protein... more We report on the discovery of benzo-and pyridino-thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7′-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H-purin-6-ylamine).
AAPS PharmSciTech, 2003
The first step in the preparation of liposomes is to dissolve the lipids into organic solvent. Th... more The first step in the preparation of liposomes is to dissolve the lipids into organic solvent. The solvent must be volatile and have high solubility for lipids. This requirement has introduced safety issues. Chloroform and ether are the commonly used solvents. Chloroform was used as an anesthetic during surgery for many years before its harmful effects on the liver and kidney were recognized. Based on animal studies, the Department of Health and Human Services (DHHS), the International Agency for Research on Cancer (IARC), and the Environmental Protection Agency (EPA) have determined that chloroform is possibly carcinogenic to humans. The breakdown products of chloroform in air include hydrogen chloride and phosgene, which are even more toxic than chloroform. Ether, while relatively nontoxic, is highly flammable. Both of these agents have been abandoned as anesthetics for clinical use. Even though only a small amount of residue would exist in liposomal formulations, it is still not acceptable. Because chloroform and ether evaporate very quickly, they would be harmful to the lab workers who were exposed to them. Chloroform is also toxic to aquatic and soil organisms after entering the natural environment, which is a probable consequence of using it as a solvent. 7,8,9
ACS Medicinal Chemistry Letters
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer... more Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.
ACS Medicinal Chemistry Letters
Bioorganic & Medicinal Chemistry Letters
Journal of pharmaceutical sciences, Jan 5, 2017
The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and p... more The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and physicochemical properties. Among the physicochemical properties, solubility and dissolution rate often are the most critical factors affecting the oral bioavailability of a compound. The increasing challenge for the pharmaceutical industry is to achieve reasonable oral bioavailability of poorly water-soluble drug candidates. G-F is a potent and selective B-Raf (rapidly accelerated fibrosarcoma) inhibitor with poor water solubility and moderate permeability, which resulted in an absorption-limited exposure in preclinical safety studies. The intrinsic solubility of G-F is 8 μg/mL (i.e., 0.0188 nM). In this study, pH adjustment combined with cosolvency, micellization, or complexation was applied as a technique to enhance the solubility of G-F. pH 9.5 and 4 buffers were selected to combine with the solubilization agents based on G-F's acidic pKa of 7.47. The solubilization power of each ...
Toxicology and applied pharmacology, Jan 13, 2017
Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdraw... more Drug-induced liver injury (DILI) has been the most frequent cause of post-marketing drug withdrawals in the last 50years. The multifactorial nature of events that precede severe liver injury in human patients is difficult to model in rodents due to a variety of confounding or contributing factors that include disease state, concurrent medications, and translational species differences. In retrospective analyses, a consistent risk factor for DILI has been the inhibition of the Bile Salt Export Pump (BSEP). One compound known for potent BSEP inhibition and severe DILI is troglitazone. The purpose of the current study is to determine if serum profiling of 19 individual bile acids by liquid chromatography-mass spectrometry (LC/MS) can detect perturbations in bile acid homeostasis in rats after acute intravenous (IV) administration of vehicle or 5, 25, or 50mg/kg troglitazone. Minimal serum transaminase elevations (approximately two-fold) were observed with no evidence of microscopic liv...
Journal of medicinal chemistry, Jan 11, 2017
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interest... more Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781; TR-FRET IC50 = 0.94 nM, BRET IC50 = 6.2 nM, BRD4(1) IC50 = 5,100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays anti-tumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a...
Bioorganic & medicinal chemistry letters, Jul 1, 2017
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged sc... more A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.
Journal of pharmaceutical and biomedical analysis, Jan 18, 2017
Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently use... more Polyethylene glycol (PEG) based formulation and polyvinylchloride (PVC) tubing are frequently used for drug delivery and administration. The compatibility of a parenteral drug microdose formulation in intravenous infusion (IV) devices was studied to support the clinical determination of absolute bioavailability by the microdosing method. The investigational microdose formulation containing PEG was found prone to significant loss of potency within hours of storage in the PVC IV tubing due to degradation. Degradation occurred only when both PEG and PVC tubing were present. The degradation product could not be detected by LC/MS due to the significant interference from the high concentration of PEG (4%) matrix and the extremely low level of drug (0.6ppm). To obtain structural information of the degradation impurity and understand the cause of the degradation, a simple heart-cutting 2D-LC/MS approach was utilized to effectively separate the impurity from the complex PEG oligomers and ove...