5 research outputs found
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Novel HDAC6 inhibitors increase tubulin acetylation and rescue axonal transport of mitochondria in a model of Charcot-Marie-Tooth Type 2F
Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age- related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme HDAC6 has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models but better drug candidates are still needed. Here we report the development and characterisation of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot- Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.Funding for this work was provided by Takeda Development Centre Europe Ltd. M.P.C. is funded by the John and Lucille van Geest Foundation
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Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.
BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation
Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)Âcyclobutyl]Âacetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist
A series of tetrahydroÂnaphthyridine
derivatives as novel RORγt inverse agonists were designed and
synthesized. We reduced the lipophilicity of tetrahydroÂisoquinoline
compound <b>1</b> by replacement of the trimethylsilyl group
and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable
in vitro activity. Consideration of LLE values in the subsequent optimization
of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)Âcarbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6Â(5<i>H</i>)-yl}Âcarbonyl)Âcyclobutyl]Âacetic acid, TAK-828F
(<b>10</b>), which showed potent RORγt inverse agonistic
activity, excellent selectivity against other ROR isoforms and nuclear
receptors, and a good pharmacokinetic profile. In animal studies,
oral administration of compound <b>10</b> exhibited robust and
dose-dependent inhibition of IL-17A cytokine expression in a mouse
IL23-induced gene expression assay. Furthermore, development of clinical
symptoms in a mouse experimental autoimmune encephalomyelitis model
was significantly reduced. Compound <b>10</b> was selected as
a clinical compound for the treatment of Th17-driven autoimmune diseases
Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)Âcyclobutyl]Âacetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist
A series of tetrahydroÂnaphthyridine
derivatives as novel RORγt inverse agonists were designed and
synthesized. We reduced the lipophilicity of tetrahydroÂisoquinoline
compound <b>1</b> by replacement of the trimethylsilyl group
and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable
in vitro activity. Consideration of LLE values in the subsequent optimization
of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)Âcarbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6Â(5<i>H</i>)-yl}Âcarbonyl)Âcyclobutyl]Âacetic acid, TAK-828F
(<b>10</b>), which showed potent RORγt inverse agonistic
activity, excellent selectivity against other ROR isoforms and nuclear
receptors, and a good pharmacokinetic profile. In animal studies,
oral administration of compound <b>10</b> exhibited robust and
dose-dependent inhibition of IL-17A cytokine expression in a mouse
IL23-induced gene expression assay. Furthermore, development of clinical
symptoms in a mouse experimental autoimmune encephalomyelitis model
was significantly reduced. Compound <b>10</b> was selected as
a clinical compound for the treatment of Th17-driven autoimmune diseases