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1.
Mol Pharm ; 21(3): 1321-1333, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38334418

RESUMEN

Attractive self-interactions and reversible self-association are implicated in many problematic solution behaviors for therapeutic proteins, such as irreversible aggregation, elevated viscosity, phase separation, and opalescence. Protein self-interactions and reversible oligomerization of two Fc-fusion proteins (monovalent and bivalent) and the corresponding fusion partner protein were characterized experimentally with static and dynamic light scattering as a function of pH (5 and 6.5) and ionic strength (10 mM to at least 300 mM). The fusion partner protein and monovalent Fc-fusion each displayed net attractive electrostatic self-interactions at pH 6.5 and net repulsive electrostatic self-interactions at pH 5. Solutions of the bivalent Fc-fusion contained higher molecular weight species that prevented quantification of typical interaction parameters (B22 and kD). All three of the proteins displayed reversible self-association at pH 6.5, where oligomers dissociated with increased ionic strength. Coarse-grained molecular simulations were used to model the self-interactions measured experimentally, assess net self-interactions for the bivalent Fc-fusion, and probe the specific electrostatic interactions between charged amino acids that were involved in attractive electrostatic self-interactions. Mayer-weighted pairwise electrostatic energies from the simulations suggested that attractive electrostatic self-interactions at pH 6.5 for the two Fc-fusion proteins were due to cross-domain interactions between the fusion partner domain(s) and the Fc domain.


Asunto(s)
Aminoácidos , Anticuerpos Monoclonales , Anticuerpos Monoclonales/química , Dispersión Dinámica de Luz , Concentración Osmolar , Concentración de Iones de Hidrógeno
2.
J Nurs Adm ; 52(12): 679-684, 2022 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-36409262

RESUMEN

OBJECTIVE: The aim of this study was to analyze the perceptions of core team members implementing patient-centered medical home (PCMH) within the Veterans Health Administration regarding delegation of work. BACKGROUND: Significant overlap exists in the performance of work tasks among PCMH team members (primary care providers, RNs, clinical associates, clerks), and scant literature exists on appropriate delegation within PCMH teams. METHODS: This study conducted used a quantitative and qualitative analysis of 4254 respondents to a 2018 survey. RESULTS: Primary care providers rely heavily on team members, and nurses report being relied upon at high levels. Lack of role clarity and a perceived need for a team leader were concerns voiced by participants. CONCLUSIONS: Findings indicated a need for clear guidance on roles and responsibilities within the team. Patient-centered medical home team members need information about the scope of practice of each professional group to allow providers to function at the top of their scope of practice and ensure effective delegation.


Asunto(s)
Grupo de Atención al Paciente , Atención Primaria de Salud , Estados Unidos , Humanos , United States Department of Veterans Affairs , Atención Dirigida al Paciente , Encuestas y Cuestionarios
3.
Mol Pharm ; 18(7): 2455-2469, 2021 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-34165309

RESUMEN

The process of bringing a drug to market involves innumerable decisions to refine a concept into a final product. The final product goes through extensive research and development to meet the target product profile and to obtain a product that is manufacturable at scale. Historically, this process often feels inflexible and linear, as ideas and development paths are eliminated early on to allow focus on the workstream with the highest probability of success. Carrying multiple options early in development is both time-consuming and resource-intensive. Similarly, changing development pathways after significant investment carries a high "penalty of change" (PoC), which makes pivoting to a new concept late in development inhibitory. Can drug product (DP) development be made more flexible? The authors believe that combining a nonlinear DP development approach, leveraging state-of-the art data sciences, and using emerging process and measurement technologies will offer enhanced flexibility and should become the new normal. Through the use of iterative DP evaluation, "smart" clinical studies, artificial intelligence, novel characterization techniques, automation, and data collection/modeling/interpretation, it should be possible to significantly reduce the PoC during development. In this Perspective, a review of ideas/techniques along with supporting technologies that can be applied at each stage of DP development is shared. It is further discussed how these contribute to an improved and flexible DP development through the acceleration of the iterative build-measure-learn cycle in laboratories and clinical trials.


Asunto(s)
Inteligencia Artificial , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación de Medicamentos/normas , Preparaciones Farmacéuticas/normas , Química Farmacéutica , Ensayos Clínicos como Asunto , Humanos
4.
Bioorg Med Chem Lett ; 49: 128314, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34391891

RESUMEN

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Naftiridinas/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Animales , Dominio Catalítico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Naftiridinas/síntesis química , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirroles/síntesis química , Pirroles/metabolismo , Pirroles/farmacocinética , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 47: 128214, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34166782

RESUMEN

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.


Asunto(s)
Compuestos Aza/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indoles/farmacología , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indoles/síntesis química , Indoles/química , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad
6.
Bioorg Med Chem Lett ; 27(12): 2721-2726, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28501511

RESUMEN

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.


Asunto(s)
Inflamación/tratamiento farmacológico , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Administración Oral , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Imidazoles/farmacología , Inflamación/enzimología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Quinazolinas/administración & dosificación , Quinazolinas/química , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad
7.
J Pharm Sci ; 112(11): 2778-2782, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37478972

RESUMEN

Biological therapeutics are major contributors to the pharmaceutical pipeline and continue to grow in sales and scope. Additionally, the field's understanding of cancer biology has advanced such that biopharmaceuticals can harness the power of the immune system for oncology treatments. Several of these novel therapeutics are engineered versions of naturally occurring proteins designed to improve therapeutic properties including potency, target engagement and half-life extension. Cytokines, such as interferons and interleukins, are a broad class of signaling proteins which modulate the body's immune response; engineered cytokines have entered the clinic as promising new immuno-oncology therapies. While these therapies hold great promise, their additional structural complexity introduces analytical challenges, and traditional analytical platforms may be ill-suited to effectively assess product development risks. Further, the pharmaceutical industry relies on streamlining approaches for high-throughput experimentation to achieve speed and efficiency for the discovery and development of new modalities. These demands necessitate the use of state-of-the-art techniques to rapidly characterize these new modalities and guide process development and optimization. Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS) is a rapid, sensitive and automatable technique amenable for high-throughput analysis of proteins. In this work, we have developed an automated MALDI-MS platform to prepare, acquire and analyze molecular degradation in engineered PEGylated cytokines formulation samples. This orthogonal technique integrated seamlessly with current developability risk assessment workflows, ultimately enabling selection of a final formulation strategy for clinical development.

8.
Mol Cancer Ther ; 21(2): 282-293, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34815361

RESUMEN

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective antitumor activity. Mechanistic studies in immune-deficient mice suggested that antitumor activity of intratumorally dosed STING agonists is in part due to necrosis and/or innate immune responses such as TNF-α activity, but development of a robust adaptive antitumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models showed that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.


Asunto(s)
Inmunidad Innata/inmunología , Inmunoterapia/métodos , Interferones/metabolismo , Neoplasias/inmunología , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones
9.
J Med Chem ; 65(8): 6001-6016, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35239336

RESUMEN

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.


Asunto(s)
Inhibidores Enzimáticos , Éteres Cíclicos , Amidas , Ciclización , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo
10.
Pharmaceutics ; 13(7)2021 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-34371726

RESUMEN

Amorphous solid dispersions (ASD) have become a well-established strategy to improve exposure for compounds with insufficient aqueous solubility. Of methods to generate ASDs, spray drying is a leading route due to its relative simplicity, availability of equipment, and commercial scale capacity. However, the broader industry adoption of spray drying has revealed potential limitations, including the inability to process compounds with low solubility in volatile solvents, inconsistent molecular uniformity of spray dried amorphous dispersions, variable physical properties across batches and scales, and challenges containing potent compounds. In contrast, generating ASDs via co-precipitation to yield co-precipitated amorphous dispersions (cPAD) offers solutions to many of those challenges and has been shown to achieve ASDs comparable to those manufactured via spray drying. This manuscript applies co-precipitation for early safety studies, developing a streamlined process to achieve material suitable for dosing as a suspension in conventional toxicity studies. Development targets involved achieving a rapid, safely contained process for generating ASDs with high recovery yields. Furthermore, a hierarchical particle approach was used to generate composite particles where the cPAD material is incorporated in a matrix of water-soluble excipients to allow for rapid re-dispersibility in the safety study vehicle to achieve a uniform suspension for consistent dosing. Adopting such an approach yielded a co-precipitated amorphous dispersion with comparable stability, thermal properties, and in vivo pharmacokinetics to spray dried amorphous materials of the same composition.

11.
SLAS Discov ; 26(1): 88-99, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32844715

RESUMEN

Hematopoietic progenitor kinase 1 (HPK1), also referred to as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a serine/threonine kinase that negatively regulates T-cell signaling by phosphorylating Ser376 of Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76), a critical mediator of T-cell receptor activation. HPK1 loss of function mouse models demonstrated enhanced immune cell activation and beneficial antitumor activity. To enable discovery and functional characterization of high-affinity small-molecule HPK1 inhibitors, we have established high-throughput biochemical, cell-based, and novel pharmacodynamic (PD) assays. Kinase activity-based time-resolved fluorescence energy transfer (TR-FRET) assays were established as the primary biochemical approach to screen for potent inhibitors and assess selectivity against members of MAP4K and other closely related kinases. A proximal target engagement (TE) assay quantifying pSLP-76 levels as a readout and a distal assay measuring IL-2 secretion as a functional response were established using human peripheral blood mononuclear cells (PBMCs) from two healthy donors. Significant correlations between biochemical and cellular assays as well as excellent correlation between the two donors for the cellular assays were observed. pSLP-76 levels were further used as a PD marker in the preclinical murine model. This effort required the development of a novel ultrasensitive single-molecule array (SiMoA) assay to monitor pSLP-76 changes in mouse spleen.


Asunto(s)
Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Animales , Línea Celular , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
12.
Oncoimmunology ; 10(1): 1896643, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33796403

RESUMEN

Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite produced by cyclooxygenase (COX)-1/2, has been shown to impair anti-tumor immunity through engagement with one or more E-type prostanoid receptors (EP1-4). Specific targeting of EP receptors, as opposed to COX-1/2 inhibition, has been proposed to achieve preferential antagonism of PGE2-mediated immune suppression. Here we describe the anti-tumor activity of MF-766, a potent and highly selective small-molecule inhibitor of the EP4 receptor. EP4 inhibition by MF-766 synergistically improved the efficacy of anti-programmed cell death protein 1 (PD-1) therapy in CT26 and EMT6 syngeneic tumor mouse models. Multiparameter flow cytometry analysis revealed that treatment with MF-766 promoted the infiltration of CD8+ T cells, natural killer (NK) cells and conventional dendritic cells (cDCs), induced M1-like macrophage reprogramming, and reduced granulocytic myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME). In vitro experiments demonstrated that MF-766 restored PGE2-mediated inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in THP-1 cells and human blood, and PGE2-mediated inhibition of interleukin (IL)-2-induced interferon (IFN)-γ production in human NK cells. MF-766 reversed the inhibition of IFN-γ in CD8+ T-cells by PGE2 and impaired suppression of CD8+ T-cells induced by myeloid-derived suppressor cells (MDSC)/PGE2. In translational studies using primary human tumors, MF-766 enhanced anti-CD3-stimulated IFN-γ, IL-2, and TNF-α production in primary histoculture and synergized with pembrolizumab in a PGE2 high TME. Our studies demonstrate that the combination of EP4 blockade with anti-PD-1 therapy enhances antitumor activity by differentially modulating myeloid cell, NK cell, cDC and T-cell infiltration profiles.


Asunto(s)
Linfocitos T CD8-positivos , Subtipo EP4 de Receptores de Prostaglandina E , Animales , Ciclooxigenasa 2 , Dinoprostona , Macrófagos , Ratones
13.
ACS Med Chem Lett ; 12(3): 389-396, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33738066

RESUMEN

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and N-pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound 28 is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.

14.
Bioconjug Chem ; 21(4): 764-73, 2010 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-20353169

RESUMEN

PEGylated dendrimers are attractive for biological applications due to their tunable pharmacokinetics and ability to carry multiple copies of bioactive molecules. The rapid and efficient synthesis of a robust and biodegradable PEGylated dendrimer based on a polyester-polyamide hybrid core is described. The architecture is designed to avoid destructive side reactions during dendrimer preparation while maintaining biodegradability. Therefore, a dendrimer functionalized with doxorubicin (Dox) was prepared from commercial starting materials in nine, high-yielding linear steps. Both the dendrimer and Doxil were evaluated in parallel using equimolar dosage in the treatment of C26 murine colon carcinoma, leading to statistically equivalent results with most mice tumor-free at the end of the 60 day experiment. The attractive features of this dendritic drug carrier are its simple synthesis, biodegradability, and versatility for application to a variety of drug payloads with high drug loadings.


Asunto(s)
Neoplasias del Colon/metabolismo , Dendrímeros/metabolismo , Dendrímeros/farmacocinética , Portadores de Fármacos/síntesis química , Portadores de Fármacos/farmacocinética , Diseño de Fármacos , Polietilenglicoles/metabolismo , Polietilenglicoles/farmacocinética , Animales , Neoplasias del Colon/tratamiento farmacológico , Dendrímeros/síntesis química , Modelos Animales de Enfermedad , Portadores de Fármacos/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Nylons/química , Poliésteres/química , Polietilenglicoles/síntesis química
15.
ACS Med Chem Lett ; 11(8): 1548-1554, 2020 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-32832022

RESUMEN

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

16.
ACS Med Chem Lett ; 11(2): 114-119, 2020 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-32071676

RESUMEN

The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

17.
Innate Immun ; 25(2): 132-143, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30774010

RESUMEN

Crohn's disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2-/- mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1ß secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1ß secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.


Asunto(s)
Colitis/inmunología , Enfermedad de Crohn/inmunología , Microbioma Gastrointestinal/inmunología , Inflamasomas/metabolismo , Mucosa Intestinal/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Animales , Colitis/inducido químicamente , Sulfato de Dextran , Modelos Animales de Enfermedad , Furanos/administración & dosificación , Furanos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Indenos , Interleucina-1beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Transducción de Señal , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Sulfonas
18.
ACS Med Chem Lett ; 10(11): 1530-1536, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31749906

RESUMEN

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SNAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound 16 was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound 16, rendering it a potential drug candidate.

19.
Eur J Pharm Sci ; 103: 85-93, 2017 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-28263913

RESUMEN

We employed a recently introduced class of sterol-modified lipids (SML) to produce m-PEG-DSPE containing liposome compositions with a range of cis-platinum content release rates. SML have a cholesterol succinate attached to the phosphatidylglycerol head group and a fatty acid at the 2 position. These compositions were compared to the well-studied liposome phospholipid compositions: mPEG-DSPE/Hydrogenated Soy PC/cholesterol or mPEG-DSPE/POPC/cholesterol to determine the effect of the cis-platinum release extent on C26 tumor proliferation in the BALB/c colon carcinoma mouse model. The release rates of cis-platinum from liposomes composed of SML are a function of the acyl chain length. SML-liposomes with shorter acyl chain lengths C-8 provided more rapid cisplatin release, lower in vitro IC50, and were easier to formulate compared to liposomes using traditional phospholipid compositions. Similar to other liposome cis-platinum formulations, the half-life of m-PEG-DSPE SML liposome cisplatin is substantially longer than the free drug. This resulted in a higher tumor cisplatin concentration at 48h post-dosing compared to the free drug and higher Pt-DNA adducts in the tumor. Moreover, the maximum tolerated dose of the liposome formulations where up to four fold greater than the free drug. Using X-ray fluorescence spectroscopy on tumor sections, we compared the location of platinum, to the location of a fluorescence lipid incorporated in the liposomes. The liposome platinum co-localized with the fluorescent lipid and both were non-uniformly distributed in the tumor. Non-encapsulated Cis-platinum, albeit at a low concentration, was more uniformly distributed thorough the tumor. Three liposome formulations, including the well-studied hydrogenated HSPC composition, had better antitumor activity in the murine colon 26 carcinoma model as compared to the free drug at the same dose but the SML liposome platinum formulations did not perform better than the HSPC formulation.


Asunto(s)
Antineoplásicos/administración & dosificación , Colesterol/química , Cisplatino/administración & dosificación , Fosfolípidos/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cisplatino/química , Cisplatino/farmacología , Neoplasias del Colon/tratamiento farmacológico , Preparaciones de Acción Retardada , Femenino , Semivida , Humanos , Liposomas , Dosis Máxima Tolerada , Ratones Endogámicos BALB C , Distribución Tisular
20.
Cell Rep ; 17(12): 3206-3218, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-28009290

RESUMEN

Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Timocitos/inmunología , Animales , Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/genética , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/terapia , Regulación de la Expresión Génica/inmunología , Reordenamiento Génico/genética , Humanos , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Células Th17/efectos de los fármacos , Células Th17/inmunología
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