2019-07-01

We demonstrated that inositol 1,3,4,5-tetrakisphosphate (IP4), the product of ITPKB, plays a critical role in redox homeostasis upon cisplatin exposure by reducing cisplatin-induced ROS through inhibition of a ROS-generating enzyme, NADPH oxidase 4 (NOX4), which promotes cisplatin-resistant tumor growth.

B cells from ItpkB −/− mice have features of anergic B cells that arise in models of self-tolerance, suggesting that ITPKB-deficiency can allow the positive selection of autoimmune-prone B cells. Future studies with sub-optimal Akt/mTOR inhibitor concentrations not affecting WT thymocytes but still reversing the Itpkb-/-phenotype, with complex genetic models and with inhibitors of β-selection effectors unaffected by Itpkb will be needed to more conclusively distinguish between specific causative roles for the Akt/mTORC1 and metabolic hyperactivity and mere remaining sensitivity of 2005-04-26 · cytoplasm, cytosol, nucleus, inositol hexakisphosphate kinase activity, inositol-1,4,5-trisphosphate 3-kinase activity, kinase activity, cellular response to calcium ion, inositol phosphate biosynthetic process, inositol phosphate metabolic process, inositol trisphosphate metabolic process In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP 3 to negatively regulate and thereby tightly control Ca 2 1 fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca 21 Does Itpkb Inhibition have Therapeutic Potential in Human Diseases? The T and B cell defects in germline Itpkb −/− mice sparked efforts to develop specific and selective Itpkb small-molecule inhibitors as potential therapeutics for autoimmune disorders or transplant rejection, reviewed in detail in Ref. (8, 149). Moreover, Akt inhibition reduced RMA/S-induced ItpkB −/− NK cell hyperdegranulation to inhibitor-untreated WT NK cell levels (22.3% vs 20.7%; Figure 7A-B). The similar abilities of cell-permeable IP 4 , PI3K, or Akt inhibitors to reverse the hyperdegranulation of ItpkB −/− NK cells are consistent with a model in which IP 4 limits NK cell degranulation by antagonizing NKR-induced Akt recruitment by PI3K/PIP 3 . Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease PLOS ONE , Dec 2019 Andrew T. Miller , Carol Dahlberg , Mark L. Sandberg , Ben G. Wen , Daniel R. Beisner , John A. H. Hoerter , Albert Parker , Christian Schmedt , Monique Stinson , Jacqueline Avis , et al.

Rat antigen-induced arthritis (rAIA) is a well-studied animal model of arthritis, due to its similarities with human Rheumatoid Arthritis (RA), and the involvement of T lymphocytes . The invention provides a novel class of compounds of formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or dysregulated B cell activities, particularly diseases or disorders that involve aberrant activation of inositol 1,4,5-trisphosphate 3-kinase B (ITPKb). Moreover, inhibition of ITPKB in cultured mouse neurons limits the production of amyloid peptides responsible for the formation of senile plaques. Professor Stéphane Schurmans, director of the GIGA Functional Genetics Laboratory at the University of Liège, reveals the results of his work in a study published in Brain. Compounds and compositions as itpkb inhibitors. C07D491/048 - C07D413/14 - containing three or more hetero rings. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death.

Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD).

2019-12-03

ITPKB upregulation is associated with cisplatin resistance in diverse cancer cell lines and primary patient samples. Itpkb-deficient B lymphocytes had the phenotypic and functional features of tolerant B lymphocytes and showed enhanced activity of store-operated Ca 2+ channels after B lymphocyte receptor Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin, suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance. Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that induced by the inhibition of NFAT using Targeting ITPKB with shRNA or its small molecule inhibitor resulted in attenuation of NOX4 activity, imbalanced redox status, and sensitized cancer cells to cisplatin treatment in patient-derived xenografts.

Aug 1, 2016 These data indicate an inhibitory effect of. miR-132 over soluble and aggregated Ab species formation. miR-132 controls TAU phosphorylation.

It also potently inhibits Itpka, as well as Itpkc.

Mounting evidence suggests that ITPKB is implicated in hematopoiesis.
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The activity of this encoded protein is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling. GNF362 is a selective, potent, and orally bioavailable inhibitor of Itpkb (IC 50 =9 nM). It reveals a novel strategy to treat autoimmune disease. GNF362 binds to the ATP-binding pocket of Itpkb. It also potently inhibits Itpka, as well as Itpkc.

“Itpkb pathway inhibition increases intracellular Ca 2+, induces apoptosis of activated T cells, and can control T-cell–mediated autoimmunity,” they continued. Thus, Dr Thangavelu and co-investigators conducted a study in which they used genetic and pharmacologic methods to inhibit Itpkb signaling as a means of controlling GVHD. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T-cells, and can control T-cell mediated autoimmunity. Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD).
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GNF362 is a selective, potent, and orally bioavailable inhibitor of inositol trisphosphate 3’ kinase B (Itpkb) with an IC50 of 9 nM. GNF362 also inhibits Itpka and Itpkc with IC50 values of 20 nM and 19 nM, respectively.

Here, we employed mentary Fig. 4). Addition of a MEK1/2 inhibitor to the culture medium completely prevented overproduction of amyloid-β pep- tides in GFP-Itpkb transfected cells, itpka, itpkb, itpkc, insp3 3-kinase, ip3k, ip3k-a, ip3kb, insp3kinase, ins(1,4,5)p3 kinase, inositol 1,4,5-trisphosphate 3-kinase c, more. top print hide 112 entries GNF362 is a selective, potent, and orally bioavailable inhibitor of inositol trisphosphate 3' kinase B (Itpkb) with an IC50 of 9 nM. GNF362 also inhibits Itpka and 2020年12月24日 Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown True or False: Vedolizumab could help prevent aGVHD by inhibiting the True or False: Itpkb signaling is essential to drive acute GVHD pathogenesis and Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that induced Pharmacological inhibition of ITPKB in mice reduced both LPS-induced tissue swelling and the severity of inflammatory arthritis to a similar extent as that Jan 8, 2018 Rapamycin and rapalogs allosterically inhibit mTORC1 activity by rapamycin blocks phenotypic HSC expansion in Itpkb-knockout mice, The observation that chemical inhibition of ITPKB also sensitized cells to that exogenously added InsP5 inhibited phosphorylation of Akt in ovarian cancer line May 29, 2020 Ibrutinib is a highly active and selectively irreversible inhibitor of BTK, found that a patient with ITPKB mutation-driven CLL experienced RT ITPKB. Inositol 1,4,5-trisphosphate 3-kinase B. 1q42.13.