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1

Article

SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition

Hanson, Jesse E ; La, Hank ; Plise, Emile ; [et al.]

2013

ISSN: 1932-6203

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Language: English

In: PloS one, 2013, Vol.8 (7), p.e69964

Description: Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer's disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology.

Subject(s): Acids ; Acquired immune deficiency syndrome ; AIDS ; Alzheimer's disease ; Animal cognition ; Animals ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters - metabolism ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Availability ; Behavior, Animal - drug effects ; Behavioral plasticity ; Biology ; Blood-brain barrier ; Brain ; Brain - drug effects ; Brain - enzymology ; Brain - metabolism ; Brain slice preparation ; CA1 Region, Hippocampal - drug effects ; CA1 Region, Hippocampal - physiology ; Central nervous system ; Chromatin ; Cognition ; Cognition - drug effects ; Conditioning (Psychology) - drug effects ; Disease ; Efflux ; Excitability ; Excitation ; Excitatory Postsynaptic Potentials - drug effects ; Experiments ; Fear - drug effects ; Gene expression ; Hippocampus ; Histone deacetylase ; Histone Deacetylases - metabolism ; Humans ; Hydroxamic acid ; Hydroxamic Acids - administration & dosage ; Hydroxamic Acids - pharmacokinetics ; Hydroxamic Acids - pharmacology ; Immunological synapses ; Impact analysis ; In vivo methods and tests ; Inhibitory Concentration 50 ; Isoenzymes - metabolism ; Laboratory animals ; Long-term depression ; Long-term potentiation ; Long-Term Potentiation - drug effects ; Lymphoma ; Medicine ; Membranes - drug effects ; Memory ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurodegeneration ; Neurodegenerative diseases ; Neuronal Plasticity - drug effects ; Neurons ; Neurophysiology ; Neurosciences ; Non-Hodgkin's lymphomas ; Pharmacology ; Phenotype ; Potentiation ; Rats ; Rats, Sprague-Dawley ; Rodents ; Substrates ; Synapses ; Synapses - drug effects ; Synapses - physiology ; Synaptic depression ; Synaptic plasticity ; Synaptic strength ; T cells ; T-cell lymphoma

ISSN: 1932-6203

E-ISSN: 1932-6203

DOI: 10.1371/journal.pone.0069964

Source: Academic Search Ultimate

Source: PubMed Central

Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery

URL: https://www.ncbi.nlm.nih.gov/pubmed/23922875$$D View this record in MEDLINE/PubMed

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2

Article

Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

Hanan, Emily J ; Eigenbrot, Charles ; Bryan, Marian C ; [et al.]

2014

ISSN: 0022-2623

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Language: English

In: Journal of medicinal chemistry, 2014-12-11, Vol.57 (23), p.10176-10191

Description: Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.

Subject(s): 60 APPLIED LIFE SCIENCES ; Amino Acid Substitution ; Aminopyridines - chemical synthesis ; Aminopyridines - therapeutic use ; BASIC BIOLOGICAL SCIENCES ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Crystallography, X-Ray ; Drug Resistance, Neoplasm ; High-Throughput Screening Assays ; Humans ; Lung Neoplasms - drug therapy ; Methionine - genetics ; Mutation ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - therapeutic use ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Threonine - genetics

ISSN: 0022-2623

E-ISSN: 1520-4804

DOI: 10.1021/jm501578n

Source: Hellenic Academic Libraries Link

URL: https://www.ncbi.nlm.nih.gov/pubmed/25383627$$D View this record in MEDLINE/PubMed

URL: https://www.osti.gov/servlets/purl/1168859$$D View this record in Osti.gov

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3

Article

Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKa Polar Moiety

Ndubaku, Chudi O. ; Crawford, James J. ; Drobnick, Joy ; [et al.]

2015

ISSN: 1948-5875

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Language: English

In: ACS medicinal chemistry letters, 2015-12-10, Vol.6 (12), p.1241-1246

Description: Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pKa and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. Overall, these studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

Subject(s): 60 APPLIED LIFE SCIENCES ; hERG ; Kinase inhibitor ; Letter ; oncology ; pKa

ISSN: 1948-5875

E-ISSN: 1948-5875

DOI: 10.1021/acsmedchemlett.5b00398

Source: Hellenic Academic Libraries Link

Source: PubMed Central

URL: https://www.osti.gov/servlets/purl/1258682$$D View this record in Osti.gov

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4

Article

Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors

Parr, Brendan T ; Pastor, Richard ; Sellers, Benjamin D ; [et al.]

2020

ISSN: 1948-5875

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Language: English

In: ACS medicinal chemistry letters, 2020-04-09, Vol.11 (4), p.541-549

Description: A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug–drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme.

Subject(s): CYP inhibition ; indoleamine-2,3-dioxygenase ; Letter ; property-based drug design ; Tryptophan-2,3-dioxygenase

ISSN: 1948-5875

E-ISSN: 1948-5875

DOI: 10.1021/acsmedchemlett.0c00004

Source: Hellenic Academic Libraries Link

Source: PubMed Central

URL: https://www.ncbi.nlm.nih.gov/pubmed/32292562$$D View this record in MEDLINE/PubMed

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5

Article

In Vitro and In Vivo Evaluation of Amorphous Solid Dispersions Generated by Different Bench-Scale Processes, Using Griseofulvin as a Model Compound

Chiang, Po-Chang ; Cui, Yong ; Ran, Yingqing ; [et al.]

2013

ISSN: 1550-7416

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Language: English

In: The AAPS journal, 2013-03-02, Vol.15 (2), p.608-617

Description: 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.

Subject(s): Administration, Oral ; amorphous ; Analysis ; Animals ; bioavailability ; Biochemistry ; Biological Availability ; Biomedical and Life Sciences ; Biomedicine ; Biotechnology ; Calorimetry, Differential Scanning ; Chemistry, Pharmaceutical ; Crystallography, X-Ray ; Drug Compounding ; Drug Stability ; Freeze Drying ; general ; Griseofulvin ; Griseofulvin - administration & dosage ; Griseofulvin - chemistry ; Griseofulvin - pharmacokinetics ; in vitro ; in vivo ; Magnetic Resonance Spectroscopy ; Male ; Methylcellulose ; Methylcellulose - analogs & derivatives ; Methylcellulose - chemistry ; Pharmacology/Toxicology ; Pharmacy ; Polymers ; Powder Diffraction ; Production processes ; Rats ; Rats, Sprague-Dawley ; Research Article ; solid dispersion ; Solubility ; Technology, Pharmaceutical - methods ; Thermodynamics ; Thermogravimetry

ISSN: 1550-7416

E-ISSN: 1550-7416

DOI: 10.1208/s12248-013-9469-3

Source: PubMed Central

Source: Alma/SFX Local Collection

URL: https://www.ncbi.nlm.nih.gov/pubmed/23456436$$D View this record in MEDLINE/PubMed

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6

Article

Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR

Bryan, Marian C ; Burdick, Daniel J ; Chan, Bryan K ; [et al.]

2016

ISSN: 1948-5875

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Language: English

In: ACS medicinal chemistry letters, 2016-01-14, Vol.7 (1), p.100-104

Description: The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.

Subject(s): Letter ; Mutant EGFR ; noncovalent ; pyridone ; T790M

ISSN: 1948-5875

E-ISSN: 1948-5875

DOI: 10.1021/acsmedchemlett.5b00428

Source: Hellenic Academic Libraries Link

Source: PubMed Central

URL: https://www.ncbi.nlm.nih.gov/pubmed/26819674$$D View this record in MEDLINE/PubMed

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7

Article

Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series

Rudolph, Joachim ; Aliagas, Ignacio ; Crawford, James J ; [et al.]

2015

ISSN: 1948-5875

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Language: English

In: ACS medicinal chemistry letters, 2015-06-11, Vol.6 (6), p.711-715

Description: To increase kinase selectivity in an aminopyrazole-based PAK1 inhibitor series, analogues were designed to interact with the PAK1 deep-front pocket pre-DFG residue Thr-406, a residue that is hydrophobic in most kinases. This goal was achieved by installing lactam head groups to the aminopyrazole hinge binding moiety. The corresponding analogues represent the most kinase selective ATP-competitive Group I PAK inhibitors described to date. Hydrogen bonding with the Thr-406 side chain was demonstrated by X-ray crystallography, and inhibitory activities, particularly against kinases with hydrophobic pre-DFG residues, were mitigated. Leveraging hydrogen bonding side chain interactions with polar pre-DFG residues is unprecedented, and similar strategies should be applicable to other appropriate kinases.

Subject(s): aminopyrazole ; Letter ; PAK1 kinase ; Pre-DFG residue

ISSN: 1948-5875

E-ISSN: 1948-5875

DOI: 10.1021/acsmedchemlett.5b00151

Source: Hellenic Academic Libraries Link

Source: PubMed Central

URL: https://www.ncbi.nlm.nih.gov/pubmed/26101579$$D View this record in MEDLINE/PubMed

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8

Article

Non-Covalent Wild-Type-Sparing Inhibitors of EGFR T790M

Lee, Ho-June Ho-June ; Schaefer, Gabriele Gabriele ; Heffron, Timothy P Timothy P ; [et al.]

2012

ISSN: 2159-8274

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Language: English

In: Cancer discovery, 2012-12-10, Vol.3 (2), p.168-181

Description: Approximately half of EGFR mutant non-small cell lung cancer (NSCLC) patients treated with small molecule EGFR kinase inhibitors develop drug resistance associated with the EGFR T790M “gatekeeper” substitution, prompting efforts to develop covalent EGFR inhibitors, which can effectively suppress EGFR T790M in pre-clinical models. However, these inhibitors have yet to prove clinically efficacious, and their toxicity in skin, reflecting activity against wild-type EGFR, may limit dosing required to effectively suppress EGFR T790M in vivo . While profiling sensitivity to various kinase inhibitors across a large cancer cell line panel, we identified indolocarbazole compounds, including a clinically well-tolerated FLT3 inhibitor, as potent and reversible inhibitors of EGFR T790M, which spare wild-type EGFR. These findings demonstrate the utility of broad cancer cell profiling of kinase inhibitor efficacy to identify unanticipated novel applications, and they identify indolocarbazole compounds as potentially effective EGFR inhibitors in the context of T790M-mediated drug resistance in NSCLC.

ISSN: 2159-8274

E-ISSN: 2159-8290

DOI: 10.1158/2159-8290.CD-12-0357

Source: HighWire Press (Free Journals)

Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

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9

Article

Hematopoietic stem cell maintenance and differentiation are supported by embryonic aorta-gonad-mesonephros region-derived endothelium

OHNEDA, O ; FENNIE, C ; ZHONG ZHENG ; [et al.]

1998

ISSN: 0006-4971

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Language: English

In: Blood, 1998, Vol.92 (3), p.908-919

Description: Hematopoietic stem cells are capable of extensive self-renewal and expansion, particularly during embryonic growth. Although the molecular mechanisms involved with stem cell maintenance remain mysterious, it is now clear that an intraembryonic location, the aorta-gonad-mesonephros (AGM) region, is a site of residence and, potentially, amplification of the definitive hematopoietic stem cells that eventually seed the fetal liver and adult bone marrow. Because several studies suggested that morphologically defined hematopoietic stem/progenitor cells in the AGM region appeared to be attached in clusters to the ventrally located endothelium of the dorsal aorta, we derived cell lines from this intraembryonic site using an anti-CD34 antibody to select endothelial cells. Analysis of two different AGM-derived CD34(+) cell lines revealed that one, DAS 104-8, efficiently induced fetal-liver hematopoietic stem cells to differentiate down erythroid, myeloid, and B-lymphoid pathways, but it did not mediate self-renewal of these pluripotent cells. In contrast, a second cell line, DAS 104-4, was relatively inefficient at the induction of hematopoietic differentiation. Instead, this line provoked the expansion of early hematopoietic progenitor cells of the lin-CD34(+)Sca-1(+)c-Kit+ phenotype and was proficient at maintaining fetal liver-derived hematopoietic stem cells able to competitively repopulate the bone marrow of lethally irradiated mice. These data bolster the hypothesis that the endothelium of the AGM region acts to mediate the support and differentiation of hematopoietic stem cells in vivo.

Subject(s): Abridged Index Medicus ; Animals ; Aorta - embryology ; Biological and medical sciences ; Cell Communication ; Cell Differentiation ; Cell differentiation, maturation, development, hematopoiesis ; Cell Division ; Cell Lineage ; Cell physiology ; Cell Survival ; Coculture Techniques ; Endothelium - cytology ; Endothelium - physiology ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation, Developmental ; Gonads - embryology ; Hematopoietic Stem Cells - cytology ; Liver - cytology ; Liver - embryology ; Mesonephros - embryology ; Mice ; Mice, Inbred C57BL ; Molecular and cellular biology ; Polymerase Chain Reaction ; RNA, Messenger - analysis ; Stromal Cells - physiology

ISSN: 0006-4971

E-ISSN: 1528-0020

DOI: 10.1182/blood.V92.3.908

Source: Alma/SFX Local Collection

Source: American Society of Hematology

URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2359529$$DView record in Pascal Francis

URL: https://www.ncbi.nlm.nih.gov/pubmed/9680359$$D View this record in MEDLINE/PubMed

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10

Article

Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)

Flygare, John A ; Beresini, Maureen ; Budha, Nageshwar ; [et al.]

2012

ISSN: 0022-2623

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Language: English

In: Journal of medicinal chemistry, 2012-05-10, Vol.55 (9), p.4101-4113

Description: A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K i values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.

Subject(s): Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Baculoviral IAP Repeat-Containing 3 Protein ; Binding, Competitive ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Caspases - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; Clinical Trials, Phase I as Topic ; Female ; Humans ; Inhibitor of Apoptosis Proteins - antagonists & inhibitors ; Inhibitor of Apoptosis Proteins - metabolism ; Male ; Thiadiazoles - chemical synthesis ; Thiadiazoles - chemistry ; Thiadiazoles - pharmacokinetics ; Thiadiazoles - pharmacology ; Ubiquitin-Protein Ligases

ISSN: 0022-2623

E-ISSN: 1520-4804

DOI: 10.1021/jm300060k

Source: Hellenic Academic Libraries Link

URL: https://www.ncbi.nlm.nih.gov/pubmed/22413863$$D View this record in MEDLINE/PubMed

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