A series of potent novel 8-hydroxy-3,4-dihydropyrrolo1,2-
apyrazine-1(2
H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and ...viral replication in cells. Compound
12 is active against replication of HIV-1 in cell culture with a CIC
95 of 0.31
μM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors
22–
24 with further improvement in antiviral activity.
A series of potent novel 8-hydroxy-3,4-dihydropyrrolo1,2-
apyrazine-1(2
H)-one HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound
12 is active against replication of HIV-1 in cell culture with a CIC
95 of 0.31
μM. Further SAR exploration led to the preparation of pseudosymmetrical tricyclic pyrrolopyrazine inhibitors
23 and
24 with further improvement in antiviral activity.
The synthesis and activity of novel 5-aminosubstituted 4-fluorobenzyl-8-hydroxy-1,6naphthyridine-7-carboxamide as HIV-1 integrase inhibitors is discussed. A selected derivative was efficacious ...against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques.
A series of 5-amino derivatives of 8-hydroxy1,6-naphthyridine-7-carboxamide exhibiting sub-micromolar potency against replication of HIV-1 in cell culture was identified. One of these analogs, compound
12, displayed excellent pharmacokinetic properties when dosed orally in rats and in monkeys. This compound was demonstrated to be efficacious against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques.
Bacillus Calmette-Guérin (BCG) is conventionally used as an adjuvant immunotherapy to reduce the recurrence of bladder cancer. To address the issues of efficacy and safety, an ethanol extract of ...Ganoderma lucidum (GLe) was evaluated for its interaction with BCG. In a model of premalignant human uroepithelial cells (HUC-PC), GLe exerted immediate cytotoxic effects while BCG showed a delayed response, given that both were immunological active in inducing the secretion of interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1). Synergistic cytotoxic effects were observed when cells were either coincubated with both drugs or firstly preincubated with GLe. Synergism between GLe and BCG was demonstrated to achieve a complete cytostasis in 24 hours, and such effects were progressed in the subsequent 5 days. However, the pretreatment of GLe resulted in suppression of IL-6, IL-8, and MCP-1 secretions without affecting the cytotoxicity. Given that numerous proinflammatory cytokines are associated with the high side effects toll of BCG, results herein suggested the potential implications of GL to supplement the BCG immunotherapy in bladder cancer, for better efficacy and reducing side effects.
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in ...cells.
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound
6 is active against replication of HIV with a CIC
95 of 0.31
μM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Antibody–drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ...ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these ...chimeric molecules often results in challenging physico‐chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE‐987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader‐antibody conjugate by attaching GNE‐987 to an anti‐CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen‐specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
mAb‐Mediated delivery of protein degraders. A novel strategy for attaching chimeric degrader payloads to antibodies was developed using a self‐immolative disulfide linker. A conjugate prepared using this methodology displayed strong antigen‐dependent efficacy in xenograft tumor models. The corresponding unconjugated degrader was inactive in vivo when administered at a matched dose.
Photodynamic Therapy (PDT) offers an alternative option for the treatment of nasopharyngeal carcinoma (NPC). The utilization of 3-dimensional (3D) culture model might provide better understanding of ...PDT effects on NPC cells. The aim of this in vitro study was to compare PDT effect on NPC cells using 2D and 3D models.
Two 3D culture models were established using liquid overlay method with agarose base (MCL) and hanging drop method (MCS). PDT was carried out using the combination of FosPeg® and 652 nm laser in 3D and conventional 2D models. The effects of 3D culture size and morphology on the uptake and distribution of sensitizer and gene expression were examined. Photocytotoxity, mode of cell death, and protein expression were compared for 2D and 3D models.
Regular and irregular NPC spheroids were obtained from MCL and MCS methods, respectively. A significantly down-regulation of LMP1 mRNA were observed in MCL spheroid. The sensitizer uptake in 3D spheroids was half of 2D culture. More sensitizers were required to obtain IC50 in 3D spheroids. Apoptosis, necrosis and autophagosomes were detected in PDT treated 2D and 3D cells. Different protein expression patterns were observed in 2D and 3D models.
FosPeg® PDT is effective in killing NPC cells. MCL-derived 3D spheroid model is more suitable for the evaluation of PDT killing mechanisms.
•FosPeg® mediated PDT is effective in killing NPC/C666–1 cells in 2D 3D culture models.•PDT induces different protein expression pattern in 2D 3D culture models.•Agarose-based 3D spheroids is a suitable model for studying PDT efficacy.
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A series of 10-hydroxy-7,8-dihydropyrazino1′,2′:1,5pyrrolo2,3-
dpyridazine-1,9(2
H,6
H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. ...Structure–activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study,
16, inhibits integrase strand-transfer activity with an IC
50 value of ⩽10
nM, inhibits HIV-1 replication in cell culture with an IC
95 value of 35
nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (iv
t
1/2
=
5.3
h,
F
=
17%).
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Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal ...chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.
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