The blockade of aberrant hedgehog (Hh) signaling has shown promise for therapeutic intervention in cancer. A cell-based phenotypic highthroughput screen was performed, and the lead structure (1) was identified as an inhibitor of the Hh pathway via antagonism of the Smoothened receptor (Smo). Structure-activity relationship studies led to the discovery of a potent and specific Smoothened antagonist N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4 0 -(trifluoromethoxy)biphenyl-3-carboxamide (5m, NVP-LDE225), which is currently in clinical development.

A novel series of alkoxyimino derivatives as S1P 1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure− activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing−remitting multiple sclerosis.

Background: TET proteins have been shown to target OGT to chromatin, but whether OGT regulates the TET proteins is not clear. Results: OGT regulates the subcellular localization and enzymatic activity of TET3 but not TET1 and TET2. Conclusion: The TET family of proteins is differentially regulated by OGT. Significance: We reveal a potential mechanism by which glucose metabolism regulates TET3 activity.

FTY720 is an immunomodulator with demonstrated efficacy in a phase II trial of relapsing multiple sclerosis. FTY720-phosphate, the active metabolite generated upon phosphorylation in vivo, acts as a potent agonist on four of the five known sphingosine-1-phosphate (S1P(1)) receptors. AUY954, an aminocarboxylate analog of FTY720, is a low nanomolar, monoselective agonist of the S1P(1) receptor. Due to its selectivity and pharmacokinetic profile, AUY954 is an excellent pharmacological probe of S1P(1)-dependent phenomena. Oral administration of AUY954 induces a profound and reversible reduction of circulating lymphocytes and, in combination with RAD001 (Certican/Everolimus, an mTOR inhibitor), is capable of prolonging the survival of cardiac allografts in a stringent rat transplantation model. This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation.

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Genetic improvements have significantly contributed to wheat production. Five wheat cultivars—widely grown in north China in the 1950s, 1990s, or 2010s—were grown in field experiments conducted in the 2014–2015 and 2015–2016 growing seasons. This study evaluated the genetic progress in wheat grain yield and its related traits in north China and explored how breeding and selection have influenced grain numbers and weights within spikelets in the past 60 years. The results showed that the significant increases in grain yield in the past 60 years were mainly due to increases in grain number per spike and grain weight, while spike number per m2 has not changed significantly. Improvements in thousand grain weight (TGW) from the 1950s to 2010s have occurred at four grain positions (G1 to G4). The relative contribution of G4 to TGW increased over time, but was much less than the contributions of G1, G2, and G3. Indeed, the average grain weight at G4 was much less than that of 1000 grains. The increase in grain number per spike since the 1950s was mainly due to an increase in grain number at G1, G2 and G3, with the relative contribution of grain position to grain number being G1 > G2 > G3 > G4. Dwarfing genes increased grain number per spike and grain number at G3 and G4, but not TGW. In future, yields could be boosted by enhancing grain weight at G4 and grain number at G3 and G4, while maintaining those at G1 and G2.

Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

No abstract