Fractional Hardy-Sobolev type inequalities for half spaces and John domains

As our main result we prove a variant of the fractional Hardy-Sobolev-Maz'ya inequality for half spaces. This result contains a complete answer to a recent open question by Musina and Nazarov. In the proof we apply a new version of the fractional Hardy-Sobolev inequality that we establish also for more general unbounded John domains than half spaces

MOESM4 of Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b

Additional file 4: Figure S4. Analysis of H3K9me2 at repetitive elements in ES cells treated with vitamin C. ChIP-qPCR for H3K9me2 in ES cells ± vitamin C at the repetitive element families indicated. ChIP for IgG was performed as a negative control. Data are mean ± SD. Asterisks represent P < 0.05 by t test

MOESM2 of Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b

Additional file 2: Figure S2. Analysis of H3K9me2 in G9a and GLP knockout ES cells treated with vitamin C. A) Western blot for H3K9me2 in wild-type parental TT2, G9a knockout, and GLP knockout ES cells ± vitamin C. B) Immunofluorescence for H3K9me2 in GiP ES cells ± vitamin C and untreated wild-type TT2, G9a knockout, and GLP knockout ES cells. GiP ES cells treated with vitamin C show a H3K9me2 staining pattern that is similar to G9a and GLP knockout ES cells. Scale bar represents 20 μm

MOESM1 of Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b

Additional file 1: Figure S1. Evaluation of changes in H3 PTMs following vitamin C treatment. A) Western blot for several H3 PTMs in ES cells ± vitamin C. B) Immunofluorescence for H3K9me2 and corresponding DAPI staining in untreated and vitamin C-treated ES cells. Merged images show H3K9me2 in green and DAPI staining in red. H3K9me2 immunofluorescence is also shown in Fig. 1e. Scale bar represents 20 μm

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript

6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism