Abstract The present paper describes the chemical modification of the antifungal macrolide soraphen A 1α ( 1 ) by selective removal of oxygen substituents in the south‐east ring segment. In the course of this investigation two key derivatives were prepared: 4‐demethyl‐5‐ O ‐(4‐methoxybenzyl)‐4‐episoraphen ( 6 ) and 3,5‐dideoxy‐4‐oxosoraphen ( 22 ). 6 served as precursor for 4‐demethoxysoraphen ( 19 ) and 4‐demethoxy‐5‐deoxysoraphen ( 20 ). 22 was used for the deoxygenation in positions C‐3, C‐4 and C‐5 and for the synthesis of 3,5‐didesoxysoraphen ( 24 ) as well as 4‐demethoxy‐3,5‐dideoxysoraphen ( 27 ). The comparison of the antifungicidal activity of these derivatives showed that the OH group in position C‐3 is essential for the biological activity of the soraphens.
Summary The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1β (IL-1β) release in these cells under different stimulation conditions, with the extent of IL-1β inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1β release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1β production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans. Highlights Identification of NK7-902, a CRBN molecular glue degrader of NEK7 NK7-902 fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1β production Unlike most CRBN glue degraders, NK7-902 shows activity in murine systems In vivo oral administration of NK7-902 in non-human primates leads to profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation
<div>Abstract<p>Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC<sub>90</sub> value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.</p></div>
FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
Samples from crop or animal metabolism studies of pesticides were used to evaluate the performance of the combination of analytical or narrow-bore HPLC and microplate scintillation counting (TopCount). Samples with extreme matrix content such as grain and tomato extracts from crop metabolism studies as well as extracts from hen excreta or goat urine from farm animal metabolism studies could be injected, analyzed, and quantified directly without any sample pretreatment. The minimum amount of radioactivity injected was ∼1 Bq (60 dpm). Counting times from 5 to 60 min were used for detection and quantification. These results were compared with those from classical on-line radioactivity detection and with radioactivity detection on thin-layer chromatography plates.The combination of analytical or narrow-bore HPLC and microplate scintillation counting (TopCount) offers high sensitivity and high resolution power at the same time. It could be clearly demonstrated that the combination of HPLC with microplate scintillation counting is superior to the classical on-line radioactivity detection and at least equivalent to the classical thin-layer radiochromatography regarding performance and sensitivity.
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