IC-87114

IC87114 is a PI(3)Kδ selective inhibitor with IC50 of 50 nM.

It has been reported that IC87114 reduced FMLP-induced PIP3 synthesis and chemotaxis in neutrophils[1]. IC87114 also blocked TNF1α-stimulated elastase exocytosis from neutrophils in a mouse model of inflammation. A role for PI3Kδ in TNFα-induced signaling was demonstrated by a reduction in Akt-phosphorylation and PDK1 enzyme activity upon treatment of this cell type with IC87114 [2]. In human memory T cells, IC87114 largely inhibited T-cell receptor-induced PI(3)K signaling by both naive and effector. Cytokine production in memory T cells was blocked by IC87114 from healthy and allergic donors, or from inflammatory arthritis patients [3].

References:
[1]. Workman P, van Montfort RL. PI(3) kinases: revealing the delta lady. Nat Chem Biol. 2010 Feb;6(2):82-3.
[2]. Puri KD, Doggett TA, Douangpanya J, Hou Y, Tino WT, Wilson T, Graf T, Clayton E, Turner M, Hayflick JS, Diacovo TG. Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. Blood. 2004 May 1;103(9):3448-56.
[3]. Soond DR, Bjørgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JS, Taskén K, Bunyard P, Okkenhaug K. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood. 2010 Mar 18;115(11):2203-13.

ETP-46321, a dual p110alpha/delta class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis.[Pubmed:26883061]

Biochem Pharmacol. 2016 Apr 15;106:56-69.

Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110alpha and p110delta class IA PI3K. Whereas the functioning of PI3K p110delta in immune and autoimmune reactions is well established, the role of p110alpha is less well understood. Here, a novel dual p110alpha/delta inhibitor (ETP-46321) and highly specific p110alpha (A66) or p110delta (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110delta inhibitor than by the p110alpha inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-gamma), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-gamma better than A66. The p110alpha/delta inhibitor ETP-46321, or p110alpha plus p110delta inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells. In vivo, therapeutic administration of ETP-46321 significantly inhibited responses to protein antigen as well as collagen-induced arthritis, as measured by antigen-specific antibody responses, secretion of IL-10, IL-17A or IFN-gamma, or clinical symptoms. Hence, p110alpha as well as p110delta Class IA PI3Ks are important to immune regulation; inhibition of both subunits may be an effective therapeutic approach in inflammatory autoimmune diseases like rheumatoid arthritis.

Atropisomerism and Conformational Equilibria: Impact on PI3Kdelta Inhibition of 2-((6-Amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one (IC87114) and Its Conformationally Restricted Analogs.[Pubmed:28489362]

J Med Chem. 2017 May 25;60(10):4304-4315.

IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the delta isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kdelta assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kdelta enzyme.

Pharmacological inhibition of p110delta subunit of PI3K confers protection against experimental leishmaniasis.[Pubmed:27999013]

J Antimicrob Chemother. 2017 Feb;72(2):467-477.

OBJECTIVES: This study aimed to evaluate the immuno-prophylactic and -therapeutic effect of p110delta-specific pharmacological inhibitors (CAL-101 and IC87114), either alone or in combination with amphotericin B, against experimental cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). METHODS: Female BALB/c mice were infected intravenously with Leishmania donovani or subcutaneously with Leishmania major Prophylactic treatment was initiated 24 h prior to infection, whereas therapeutic treatments with or without amphotericin B were initiated either 1 week or 2 weeks post-infection. At different times post-infection, mice were sacrificed and parasite burden, regulatory T cell (Treg) numbers and cytokine production were assessed in the liver, spleen, draining lymph nodes and footpads. In addition, direct cytolytic effects of the inhibitors on parasite growth in axenic cultures and inside infected and uninfected macrophages were also assessed. RESULTS: Prophylactic and therapeutic administration of p110delta pharmacological inhibitors significantly reduced cutaneous lesion (in CL) and parasite burdens (in VL and CL) in the spleens, livers and footpads of infected mice. The reduction in parasite burden was associated with a concomitant reduction in Treg numbers and cytokine production by liver, spleen and lymph node cells. Combined low-dose CAL-101 and amphotericin B therapy caused complete clearance of parasites in mice infected with L. donovani CONCLUSIONS: Our studies clearly show a novel therapeutic option for leishmaniasis based on CAL-101 monotherapy or CAL-101 and amphotericin B combination therapy. These observations have important and direct implications for antimicrobial immunotherapy and drug/vaccine development against leishmaniasis.

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kdelta/Akt and NFkappaB induction in a murine asthma model.[Pubmed:28855674]

Sci Rep. 2017 Aug 30;7(1):9919.

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kdelta/Akt and NF-kappaB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IkappaB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kdelta/Akt (IC-87114) respectively, or an inhibitor of NF-kappaB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.

Phosphoinositide 3-Kinase Is Involved in Mediating the Anti-inflammation Effects of Vasopressin.[Pubmed:27943011]

Inflammation. 2017 Apr;40(2):435-441.

Vasopressin possesses potent anti-inflammatory capacity. Phosphoinositide 3-kinase (PI3K) and its downstream activator Akt contribute to endogenous anti-inflammation capacity. We sought to elucidate whether PI3K is involved in mediating the anti-inflammation effects of vasopressin. Macrophages (RAW264.7 cells) were randomized to receive endotoxin, endotoxin plus vasopressin, or endotoxin plus vasopressin plus the nonselective PI3K inhibitor (LY294002) or the selective isoform inhibitor of PI3Kalpha (PIK-75), PI3Kbeta (TGX-221), PI3Kdelta (IC-87114), or PI3Kgamma (AS-252424). Compared to macrophages treated with endotoxin, the concentrations of cytokines (tumor necrosis factor-alpha, interleukin-6) and chemokine (macrophage inflammatory protein-2) in macrophages treated with endotoxin plus vasopressin were significantly lower (all P < 0.05). The concentrations of phosphorylated nuclear factor-kappaB p65 (p-NF-kappaB p65) in nuclear extracts and phosphorylated inhibitor-kappaBalpha (p-I-kappaBalpha) in cytosolic extracts as well as NF-kappaB-DNA binding activity were also lower (all P < 0.05). Of note, except for macrophages treated with endotoxin plus vasopressin plus PIK-75, the concentrations of cytokines, chemokine, p-NF-kappaB p65, and p-I-kappaBalpha as well as NF-kappaB-DNA binding activity in macrophages treated with endotoxin plus vasopressin plus LY294002, TGX-221, IC-87114, or AS-252424 were significantly higher than those in macrophages treated with endotoxin plus vasopressin (all P < 0.05). In contrast, the phosphorylated Akt concentration in macrophages treated with endotoxin plus vasopressin was significantly higher than that in macrophages treated with endotoxin or in macrophages treated with endotoxin plus vasopressin plus LY294002, TGX-221, IC-87114, or AS-252424, but not PIK-75. These data confirmed that PI3K, especially the isoforms of PI3Kbeta, PI3Kdelta, and PI3Kgamma, is involved in mediating the anti-inflammatory effects of vasopressin.