GNF362
目录号 : GC38916GNF362 是肌醇三磷酸3'激酶 B (Itpkb) 的选择性,有效且可口服生物利用的抑制剂,IC50为 9 nM。 GNF362 还抑制 Itpka 和 Itpkc,IC50 值分别为 20 nM 和 19 nM。 肌醇三磷酸3'激酶 B (Itpkb) 是一种 Ca2+ 依赖性激酶,其磷酸化 Ins (1,4,5) P3 的 3' 位置,生成肌醇 1,3,4,5-四磷酸 [Ins (1,3,4,5) P4]。
Cas No.:1003019-41-7
Sample solution is provided at 25 µL, 10mM.
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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. Inositol trisphosphate 3' kinase B (Itpkb) is a Ca2+-dependent kinase, which phosphorylates the 3' position of Ins (1,4,5) P3 to generate inositol 1,3,4,5-tetrakisphosphate [Ins (1,3,4,5) P4][1].
GNF362 (0-10 mM) blocks Ins (1,3,4,5) P4 production, enhances antigen receptor-driven Ca2+ responses and lead to apoptosis of activated T cells in an Itpkb-dependent manner in lymphocytes[1].GNF362 augments SOC responses following antigen receptor cross-linking, with an EC50 of 12 nM in primary B or T lymphocytes[1].
GNF362 (orally administration; 6 or 20 mg/kg; twice daily; 21 days) shows minimal block in antibody production but shows significant inhibition of joint swelling at 6 mg/kg, reduces inflammatory cell infiltrate, joint damage, and proteoglycan loss at 20 mg/kg[1]. Animal Model: A Lewis rat antigen-induced arthritis (rAIA) model[1]
[1]. Miller AT, et al. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci Immunol. 2019 Oct 25;4(40). pii: eaaw2707.
Cas No. | 1003019-41-7 | SDF | |
Canonical SMILES | N#CC1=CC=C(C=C1)C2=C(C=NN2)CN3C[C@H](N(CC3)C4=NC=C(C=C4)C(F)(F)F)C | ||
分子式 | C22H21F3N6 | 分子量 | 426.44 |
溶解度 | DMSO: 125 mg/mL (293.12 mM) | 储存条件 | Store at -20°C |
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1 mM | 2.345 mL | 11.725 mL | 23.45 mL |
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10 mM | 0.2345 mL | 1.1725 mL | 2.345 mL |
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Inhibition of inositol kinase B controls acute and chronic graft-versus-host disease
Blood 2020 Jan 2;135(1):28-40.PMID:31697815DOI:10.1182/blood.2019000032.
T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb-/-) T cells attenuated acute GVHD in 2 models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb-/- donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.
The actin bundling activity of ITPKA mainly accounts for its migration-promoting effect in lung cancer cells
Biosci Rep 2023 Feb 27;43(2):BSR20222150.PMID:36688944DOI:10.1042/BSR20222150.
Expression of Ins(1,4,5)P3-kinase-A (ITPKA), the neuronal isoform of Ins(1,4,5)P3-kinases, is up-regulated in many tumor types. In particular, in lung cancer cells this up-regulation is associated with bad prognosis and it has been shown that a high level of ITPKA increases migration and invasion of lung cancer cell lines. However, since ITPKA exhibits actin bundling and Ins(1,4,5)P3-kinase activity, it was not clear which of these activities account for ITPKA-promoted migration and invasion of cancer cells. To address this issue, we inhibited endogenous actin bundling activity of ITPKA in lung cancer H1299 cells by overexpressing the dominant negative mutant ITPKAL34P. Analysis of actin dynamics in filopodia as well as wound-healing migration revealed that ITPKAL34P inhibited both processes. Moreover, the formation of invasive protrusions into collagen I was strongly blocked in cells overexpressing ITPKAL34P. Furthermore, we found that ATP stimulation slightly but significantly (by 13%) increased migration of cells overexpressing ITPKA while under basal conditions up-regulation of ITPKA had no effect. In accordance with these results, overexpression of a catalytic inactive ITPKA mutant did not affect migration, and the Ins(1,4,5)P3-kinase-inhibitor GNF362 reversed the stimulating effect of ITPKA overexpression on migration. In summary, we demonstrate that under basal conditions the actin bundling activity controls ITPKA-facilitated migration and invasion and in presence of ATP the Ins(1,4,5)P3-kinase activity slightly enhances this effect.