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 …

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).

GNF362 binds to the ATP-binding pocket of Itpkb. It also potently inhibits Itpka, as well as Itpkc. 2020-10-27 · These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease. Itpkb controls hematopoietic stem cell homeostasis and prevent death from severe anemia in mice. Itpkb controls survival, proliferation and cytokine production in mouse peripheral T cells.

Itpkb inhibitor

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. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological Mechanistically, we identified that IP4 competes with the NOX4 cofactor NADPH for binding and consequently inhibits NOX4.

Patients with persistent or chronic ITP were more likely to respond to fostamatinib, a tyrosine kinase inhibitor that was approved by the FDA in 2018 for the treatment of chronic ITP, if it was initiated as second-line therapy, rather than as third line or beyond, according to an analysis of three phase III trials. 1

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. Although TCR stimulation induced a marked phosphorylation of Itpkb, inhibition of Erk signaling by U0126 not only reduced this phosphorylation but also induced dephosphorylation of Itpkb.

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

Itpkb controls survival, proliferation and cytokine production in mouse peripheral T cells. The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated B cell activities, particularly diseases or disorders that involve aberrant activation of inositol 1, 4, 5-trisphosphate 3-kinase B (ITPKb). ITPKB protein regulates inositol phosphate metabolism by phosphorylation of second messenger inositol 1,4,5-trisphosphate, which releases calcium from intracellular store in the endoplasmic reticulum by gating the inositol trisphosphate receptor. ITPKB produces Ins (1,3,4,5)P 4, which does not gate the inositol trisphosphate receptor. 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. The IUPHAR/BPS Guide to Pharmacology.

during wound healing. In particular, I studied the role of the enzyme Itpkb and its product InsP4, in 1 Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase T83467. 0.9872.
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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. Patients with persistent or chronic ITP were more likely to respond to fostamatinib, a tyrosine kinase inhibitor that was approved by the FDA in 2018 for the treatment of chronic ITP, if it was initiated as second-line therapy, rather than as third line or beyond, according to an analysis of three phase III trials. 1 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. A small-molecule pharmacological Itpkb inhibitor ameliorated aGVHD lethality and reversed established cGVHD in BO and scleroderma models, respectively associated with reduced lung M2 macrophage accumulation and lower CD4 + IFN-γ + frequency and number, as well as intracellular IL-22 level.
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Thus, targeting Itpkb may be employed as a novel Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological 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). small-molecule inhibitors BAMB-4 and GNF362 are reported to specifically inhibit ITPK isoforms (23–25). Mounting evidence sug - gests that ITPKB is implicated in hematopoiesis. ITPKB is known Figure 1. ITPKB upregulation is associated with cisplatin resistance in diverse cancer cell lines and primary patient samples.

2021-03-30

Oct 21, 2018 The team found the BTK inhibitor could diminish platelet loss in two ways: By reducing platelet destruction via inhibition of autoantibody/FcγR 9.2.1.6 Chemical inhibitor treatment on whole embryo . during wound healing.

In particular, I studied the role of the enzyme Itpkb and its product InsP4, in Mar 30, 2021 Pharmacological inhibition of ITPKB in mice reduced both LPS-induced pretreated with the potent and selective CRAC channel inhibitor.