PI4KIII beta inhibitor 3

Description: IC50 Value: 5.7 nM[1] PI4KIII beta inhibitor 3, 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1-carboxamide, is a novel and high effective PI4KIII beta inhibitor. in vitro: The most effective test compound, the compound of formula 3 (PI4KIII beta inhibitor 3), inhibited IL2 and IFNy secretion with IC50 values of less than 1 nM in each case. Thus, the compound of formula (3) was shown to be as effective at inhibiting IL2 and IFNy secretion as conventional immunosuppressants such as cyclosporine A. IC50 on IFNy and IL-2 release of Cyclosporine A are 2nM and less than 1 nM respectively [1]. in vivo: Twelve animals received daily treatment with vehicle (1%methylcellulose), twelve others received PI4KIII beta inhibitor 3 at 40 mg/kg/d in 1% methylcellulose [1]. Clinical trial: N/A

Interplay of genes in plant-pathogen interactions: In planta expression and docking studies of a beta 1,3 glucanase gene from Piper colubrinum and a glucanase inhibitor gene from Phytophthora capsici.[Pubmed:27924129]

Physiol Mol Biol Plants. 2016 Oct;22(4):567-573.

Oomycete pathogen, Phytophthora capsici is devastating for black pepper (Piper nigrum L.) and causes foot rot disease at all stages of plant growth. Phytophthora secretes a glucanase inhibitor protein (GIP), which is capable of inhibiting defence proteins like endoglucanases. In this particular study Quantitative PCR analysis, molecular docking studies and analysis of sequences of Glucanase inhibitor protein and beta-1,3 glucanse genes were done mainly depending on the data derived from Phytophthora capsici whole genome sequencing and Piper colubrinum RNA-sequencing (RNA-Seq). Amino acid sequence length of GIP gene from P. capsici was about 353 amino acids and that of glucanase pcEGase gene from P. colubrinum was about 312 amino acids. GIP gene from P. capsici showed high level of expression at early hours of the inoculation time period and pcEGase gene showed high level of expression at 16 hpi. High level of expression of pcEGase gene at 16 hpi is an indication that the GIP gene is successfully inhibited by the glucanase protein from the plant. Moreover insilico studies gave some hint on the importance of certain sites on the surfaces of both interacting proteins that might be having a role in binding of the two proteins and subsequent reactions thereof. Insilico analysis also conclusively proved that inhibition of glucanase inhibitor protein is mainly caused by recognition of an arginine as well as an isoleucine residue during the interaction of the two proteins.

Discovery of a Phosphoinositide 3-Kinase (PI3K) beta/delta Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kbeta Potency in a PI3Kdelta-Selective Template by Targeting Nonconserved Asp856.[Pubmed:28106991]

J Med Chem. 2017 Feb 23;60(4):1555-1567.

Phosphoinositide 3-kinase (PI3K) beta signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kbeta/delta inhibitors in which PI3Kbeta potency was built in a PI3Kdelta-selective template. This work led to the discovery of a highly selective PI3Kbeta/delta inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.[Pubmed:27933948]

J Med Chem. 2016 Dec 8;59(23):10435-10450.

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Abeta levels in rats and nonhuman primates and CSF Abeta levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Na(+)/H(+) exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous beta-globin knockout thalassemic mice.[Pubmed:27995414]

Mol Cell Biochem. 2017 Mar;427(1-2):201-208.

Recent investigation has shown that the liver-derived iron-regulating hormone, hepcidin, can potentiate intestinal calcium absorption in hemizygous beta-globin knockout thalassemic (BKO) mice. Since the upregulation of Fe(2+) and H(+) cotransporter, divalent metal transporter (DMT)-1, has been shown to correlate with thalassemia-induced intestinal calcium absorption impairment, the inhibition of the apical Na(+)/H(+) exchanger (NHE)-3 that is essential for cytoplasmic pH regulation and transepithelial sodium absorption was hypothesized to negatively affect hepcidin action. Herein, the positive effect of hepcidin on the duodenal calcium transport was evaluated using Ussing chamber technique. The results showed that BKO mice had lower absorptive surface area and duodenal calcium transport than wild-type mice. Besides, paracellular transport of zinc in BKO mice was compromised. Hepcidin administration completely restored calcium transport. Since this hepcidin action was totally abolished by inhibitors of the basolateral calcium transporters, Na(+)/Ca(2+) exchanger (NCX1) and plasma membrane Ca(2+)-ATPase (PMCA1b), the enhanced calcium flux potentially occurred through the transcellular pathway rather than paracellular pathway. Interestingly, the selective NHE3 inhibitor, 100 nM tenapanor, markedly inhibited hepcidin-enhanced calcium transport. Accordingly, hepcidin is one of the promising therapeutic agents for calcium malabsorption in beta-thalassemia. It mainly stimulates the transcellular calcium transport across the duodenal epithelium in an NHE3-dependent manner.