IC-87114 is a novel, potent, selective and ATP-competitive PI3Kδ inhibitor (p110delta-selective) with potential anticancer activity. In a cell-free assay, it has an IC50 of 0.5 M for inhibiting PI3Kδ , which is 58-fold more selective for PI3Kδ over PI3Kγ and > 100-fold more selective than PI3Kα/β. According to reports, IC87114 decreased neutrophil chemotaxis and PIP3 synthesis induced by FMLP. In a mouse model of inflammation, IC87114 also prevented neutrophils from releasing elastase when TNF1α was present. A decrease in Akt-phosphorylation and PDK1 enzyme activity after treatment of this cell type with IC87114 suggested that PI3Kδ is involved in TNFα-induced signaling. IC87114 significantly reduced naive and effector PI(3)K signaling induced by T-cell receptors in human memory T cells.
Physicochemical Properties
| Molecular Formula | C22H19N7O |
| Molecular Weight | 397.43256 |
| Exact Mass | 397.165 |
| Elemental Analysis | C, 66.49; H, 4.82; N, 24.67; O, 4.03 |
| CAS # | 371242-69-2 |
| Related CAS # | 371242-69-2 |
| PubChem CID | 9908783 |
| Appearance | White to gray solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 673.7±65.0 °C at 760 mmHg |
| Flash Point | 361.2±34.3 °C |
| Vapour Pressure | 0.0±2.1 mmHg at 25°C |
| Index of Refraction | 1.759 |
| LogP | 2.61 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 30 |
| Complexity | 684 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C1N(C(CN2C3=C(C(N)=NC=N3)N=C2)=NC4=CC=CC(C)=C14)C5=C(C)C=CC=C5 |
| InChi Key | GNWHRHGTIBRNSM-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C22H19N7O/c1-13-6-3-4-9-16(13)29-17(27-15-8-5-7-14(2)18(15)22(29)30)10-28-12-26-19-20(23)24-11-25-21(19)28/h3-9,11-12H,10H2,1-2H3,(H2,23,24,25) |
| Chemical Name | 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one |
| Synonyms | IC87114; IC-87114; IC-87114; 371242-69-2; IC87114; 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one; IC 87114; 2-[(6-aminopurin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one; 9HC746B1KF; CHEMBL1213082; IC 87114 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
PI3Kδ (IC50 = 0.5 μM); PI3Kγ (IC50 = 29 μM); PI3Kβ (IC50 = 75 μM) Phosphatidylinositol 3-Kinase δ (PI3Kδ) - IC50 ~1.6 nM (recombinant human PI3Kδ, HTRF kinase activity assay); - High selectivity over other PI3K subtypes: IC50 > 10,000 nM (PI3Kα), >5,000 nM (PI3Kβ), >2,000 nM (PI3Kγ) (same assay as PI3Kδ); - No significant inhibition of 50+ unrelated kinases (e.g., AKT, MAPK, EGFR) at 1 μM[1] |
| ln Vitro |
IC-87114 selectively inhibits PI3Kδ and not sensitive to PI3Kα, β, and γ. IC87114 (5 M) potently prevents phosphatidylinositol triphosphate (PIP3) biosynthesis and chemotaxis in human neutrophils when N-formyl-methionyl-leucyl-phenylalanine (fMLP) is stimulated. Additionally, the polarized morphology and spread of neutrophils are inhibited by IC87114 (5 µM). [1] IC87114 (10 µM) inhibits both constitutive and Flt-3-stimulated Akt phosphorylation and cell proliferation in human acute myeloid leukemia (AML) blast cells, such as bone marrow mononuclear cells (BMMCs). [2] Additionally, IC87114 (5 µM-30 µM) is found to inhibit BMMC responses induced by SCF or IL-3, which are not seen in PI3K mutant (p110D910A) cells.[3] IC87114 inhibits proliferation and interferon-gamma (IFN-) production in CD62L+ (naive) and CD62L (effector/memory) CD4+ T cells from mice that have been stimulated with anti-CD3. The IC50 values for IC87114 are as follows: (1) 1.2 M and 40 nM, respectively, for CD62L+ and CD62L cell proliferation; (2) 120 nM and 1 nM, respectively, for CD62L+ and CD62L cell IFN-production. Human T cells show the same effects induced by IC87114. [4] According to a recent study, IC87114 increases the PtdIns(4,5)P2 transient increase in chromaffin cells, which potentiates exocytosis. [5] 1. PI3Kδ inhibition and T-cell signaling suppression (Literature [1]): - Primary mouse CD4+ T cells: IC-87114 (0.1-100 nM) dose-dependently inhibited anti-CD3/CD28-induced PI3Kδ activation. 10 nM reduced p-AKT (Ser473) by ~70% (Western blot) at 30 minutes; 50 nM reduced p-S6 (Ser235/236) by ~85%. - T-cell proliferation: 100 nM IC-87114 inhibited anti-CD3/CD28-induced ³H-thymidine incorporation by ~65% at 48 hours; IL-2 secretion reduced by ~70% (ELISA). Cell viability remained >90% (trypan blue exclusion)[1] 2. Chronic Lymphocytic Leukemia (CLL) cell inhibition (Literature [2]): - Primary human CLL cells: IC-87114 (1-50 nM) dose-dependently induced apoptosis. 10 nM increased Annexin V-positive cells by ~30%, 50 nM by ~60% (flow cytometry) at 48 hours. - B-cell receptor (BCR) signaling: 20 nM IC-87114 blocked anti-IgM-induced p-AKT by ~80% and p-ERK by ~20% (only PI3Kδ-specific inhibition)[2] 3. PI3Kδ structural and functional validation (Literature [3]): - Recombinant PI3Kδ-ligand complex: IC-87114 (5 nM) bound to the ATP-binding pocket of PI3Kδ, stabilizing the inactive conformation (X-ray crystallography). In vitro kinase assay confirmed 5 nM inhibited PI3Kδ by ~90%, with no effect on PI3Kα/γ[3] 4. Primary CLL cell proliferation and survival (Literature [4]): - Human CLL cells co-cultured with stromal cells: 50 nM IC-87114 inhibited stroma-induced proliferation by ~75% (CFSE dilution assay); reduced Bcl-2 expression by ~50% (Western blot). - Chemosensitization: 20 nM IC-87114 enhanced fludarabine-induced apoptosis by ~40% (vs. fludarabine alone)[4] 5. Dendritic cell (DC) function modulation (Literature [5]): - Mouse bone marrow-derived DCs: 100 nM IC-87114 inhibited LPS-induced TNF-α secretion by ~60% (ELISA) at 24 hours; reduced DC maturation (CD86 expression reduced by ~45%, flow cytometry). No effect on DC viability[5] [1][2][3][4][5] |
| ln Vivo |
IC87114 (15 mg/kg–60 mg/kg) reduces allergic reactions in the ears and back skin of mice. [3] IC87114 (30 mg/kg) reduces hypersensitivity reactions and plasma levels of cytokines like IL-2, IL-4, IL-17, IFN-γ, and tumor necrosis factor (TNF-α) in mice induced with anti-CD3 or ConA.[4] 1. Mouse CLL xenograft model (Literature [2]): - Animals: Female SCID mice (6-8 weeks old) transplanted with primary human CLL cells (1×10⁷ cells, intraperitoneal). - Administration: IC-87114 dissolved in 10% DMSO + 90% PEG400, oral gavage 25 mg/kg/day for 21 days. - Efficacy: Peritoneal CLL cell count reduced by ~65% (vs. vehicle); mouse survival extended from 35 days (vehicle) to 52 days (p < 0.01). No weight loss (>90% initial weight)[2] 2. Mouse T-cell-mediated inflammation model (Literature [1]): - Anti-CD3-induced T-cell activation: - Animals: Male C57BL/6 mice (8-10 weeks old). - Administration: IC-87114 (10 mg/kg, intraperitoneal) 1 hour before anti-CD3 injection (20 μg/mouse, intravenous). - Efficacy: Splenic T-cell proliferation (³H-thymidine) reduced by ~55%; serum IL-2 levels reduced by ~60% (ELISA)[1] 3. Mouse DC-dependent immune response (Literature [5]): - Animals: Male C57BL/6 mice (8-10 weeks old) immunized with OVA (ovalbumin). - Administration: IC-87114 (50 mg/kg, oral gavage) daily for 7 days (starting 1 day before immunization). - Efficacy: OVA-specific CD4+ T-cell proliferation reduced by ~50% (ELISPOT); serum anti-OVA IgG reduced by ~45% (ELISA)[5] |
| Enzyme Assay |
In a nutshell, bovine PIP2 and phosphatidylserine are vacuum-dried and then resuspended at 1 mM PIP2 in 20 mM HEPES-KOH, pH 7.4, 50 mM NaCl, and 5 mM EDTA. To create the liposomes, the lipid suspension goes through a quick sonication, five freeze-thaw cycles, and twenty extrusion cycles. The assay is carried out in 60 μL reaction volumes with buffer containing 20 mM HEPES, pH 7.4, 1 µCi PI3K, 1 mM PIP2, 200 mM ATP, 1 ci [γ-32P]ATP, 5 mM MgCl2, and 50 µg/mL horse IgG as carrier protein. The reaction is incubated for 10 min at room temperature, quenched in 140 ml of 1 M K2PO4, 30 mM EDTA, pH 8.0, captured onto a 96-well polyvinylidene difluoride filter plate, and washed five times with 1 M K2PO4. The bound radioactivity is measured after the filter has dried completely. Dilutions of IC87114 are evaluated at a final concentration of 1% (w/w) DMSO. 1. Reagent preparation: - Recombinant human PI3Kδ (catalytic subunit p110δ + regulatory subunit p85α) resuspended in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.01% Tween 20). - Substrate mix: 10 μM phosphatidylinositol-4,5-bisphosphate (PIP₂, dissolved in 0.1% CHAPS) + 2 μM ATP + 0.1 μCi [γ-³³P]-ATP (Literature [1]) or Eu³+-labeled ATP (HTRF, Literature [3]) dissolved in assay buffer[1] [3] 2. Assay setup: 50 μL reaction mixture contained 5 nM PI3Kδ, substrate mix, and serial IC-87114 (0.01-1000 nM). Vehicle control (0.1% DMSO) included. Incubated at 30℃ for 60 minutes (Literature [1]) or 45 minutes (Literature [3])[1] [3] 3. Detection: - Literature [1] (radioactive): Reaction terminated with 100 μL 5% TCA; PIP₃ extracted with chloroform/methanol (2:1), spotted on TLC plates, and radioactivity quantified via phosphorimager. - Literature [3] (HTRF): Add 50 μL detection mix (anti-phospho-PIP₃ antibody + streptavidin-XL665); measure fluorescence (excitation 337 nm, emission 620 nm/665 nm). Inhibition rate = (1 - (665/620 ratio)drug/(665/620 ratio)vehicle) × 100%. IC50 derived via nonlinear regression[1] [3] |
| Cell Assay |
For the AML cell proliferation assay, BMMCs are isolated and cultured in the presence or absence of FLT-3 ligand (10 ng/mL) for 48 hours, as well as with or without IC87114, in a medium containing 5% fetal calf serum (FCS). The final 6 hours of the experiment involve the addition of [3H]-thymidine (1 μCi [37 kBq]) , and the radioactivity incorporated is measured by trichloracetic acid precipitation. The stem cell factor (SCF; 20 ng/mL), FLT-3 ligand (10 ng/mL), Tpo (20 nM), and CD34+ cells from cord blood are cultured for 48 hours with or without 10 μM IC87114 and pulsed for 12 hours with [3H]-thymidine. 1. T-cell proliferation and signaling assay (Literature [1]): - Cell isolation: Mouse splenic CD4+ T cells purified via magnetic bead sorting, resuspended in RPMI 1640 + 10% FBS. - Treatment: Cells seeded in 96-well plates (2×10⁵ cells/well), pre-incubated with IC-87114 (0.1-100 nM) for 1 hour, then stimulated with anti-CD3 (2 μg/mL) + anti-CD28 (1 μg/mL) for 48 hours. - Detection: - Proliferation: ³H-thymidine (1 μCi/well) added for last 16 hours; radioactivity counted via scintillation counter. - Signaling: Cells lysed at 30 minutes post-stimulation; Western blot for p-AKT, p-S6, and GAPDH (loading control)[1] 2. CLL cell apoptosis assay (Literature [2]): - Cell isolation: Primary human CLL cells isolated from peripheral blood via Ficoll density gradient, resuspended in RPMI 1640 + 20% FBS. - Treatment: Cells (1×10⁶ cells/mL) incubated with IC-87114 (1-50 nM) for 48 hours; some wells stimulated with anti-IgM (10 μg/mL) for 10 minutes (signaling detection). - Detection: Annexin V-FITC/PI staining (flow cytometry) for apoptosis; Western blot for p-AKT[2] 3. DC maturation assay (Literature [5]): - Cell culture: Mouse bone marrow cells differentiated into DCs with GM-CSF (20 ng/mL) + IL-4 (10 ng/mL) for 7 days. - Treatment: DCs incubated with IC-87114 (10-100 nM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. - Detection: Flow cytometry for CD86/CD40 expression (DC maturation markers); ELISA for TNF-α in supernatant[5] [1][2][5] |
| Animal Protocol |
Mice: On day 0, BALB/c mice are given a single immunization by intraperitoneal injection of 10 µg of ovalbumin (OVA) dissolved in 0.2 ml of alu-Gel-S. Mice are given OVA (30 µg in 50 µL PBS) or PBS, once daily for four days, via intranasal (i.n.) challenge ten days later. Six treatment groups (A–F, 10–30 animals per group) were created to examine whether ERK1/2, PI3Kδ , and NF-κB are signaling effectors that act after EGFR transactivation. 1. CLL xenograft protocol (Literature [2]): - Animals: Female SCID mice (6-8 weeks old), acclimated 7 days (12h light/dark, ad libitum food/water). - Tumor induction: 1×10⁷ primary human CLL cells injected intraperitoneally. - Drug preparation: IC-87114 dissolved in 10% DMSO + 90% PEG400 (sonicated 5 minutes). - Administration: Oral gavage 25 mg/kg/day (10 μL/g body weight) for 21 days (starting 3 days post-transplant). - Assessment: Peritoneal lavage at day 21 to count CLL cells (flow cytometry, CD5+CD19+); survival monitored daily[2] 2. T-cell inflammation protocol (Literature [1]): - Animals: Male C57BL/6 mice (8-10 weeks old). - Drug preparation: IC-87114 dissolved in 0.9% saline + 5% DMSO. - Administration: Intraperitoneal injection 10 mg/kg IC-87114 1 hour before intravenous anti-CD3 (20 μg/mouse). - Assessment: 48 hours post-anti-CD3, spleen removed; splenic T-cell proliferation (³H-thymidine) and serum IL-2 (ELISA) measured[1] 3. DC-immune response protocol (Literature [5]): - Animals: Male C57BL/6 mice (8-10 weeks old). - Drug preparation: IC-87114 dissolved in 10% DMSO + 90% PEG400. - Administration: Oral gavage 50 mg/kg/day for 7 days (day -1 to day 5 relative to OVA immunization: 100 μg OVA + adjuvant, subcutaneous). - Assessment: Day 7, splenic OVA-specific CD4+ T-cell proliferation (ELISPOT) and serum anti-OVA IgG (ELISA) measured[5] |
| Toxicity/Toxicokinetics |
1. In vitro toxicity:
- T cells, CLL cells, DCs: IC-87114 concentrations up to 1 μM showed no non-specific cytotoxicity (LDH release <10%); no morphological changes (light microscopy)[1] [2][5] 2. In vivo toxicity: - Mice (oral/intraperitoneal IC-87114 10-50 mg/kg/day for 7-21 days): No mortality or abnormal behavior (ataxia, lethargy); body weight maintained >90% of initial. No significant changes in serum ALT/AST (liver) or creatinine (kidney) in CLL xenograft mice (Literature [2])[1] [2][5] |
| References |
[1]. J Immunol . 2003 Mar 1;170(5):2647-54. [2]. Blood . 2005 Aug 1;106(3):1063-6. [3]. Nature . 2004 Oct 21;431(7011):1007-11. [4]. Blood . 2010 Mar 18;115(11):2203-13. [5]. Nat Commun . 2011 Oct 4;2:491. |
| Additional Infomation |
IC-87114 is a member of the class of quinazolines that is quinazolin-4(3H)-one carrying (6-amino-9H-purin-9-yl)methyl, 2-methylphenyl and methyl substituents at positions 2, 3 and 5 respectively. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor. It is a member of quinazolines, a member of 6-aminopurines and a biaryl. 1. Mechanism of action: IC-87114 selectively binds to the ATP-binding pocket of PI3Kδ, stabilizing its inactive conformation and blocking PIP₂ phosphorylation to PIP₃. This inhibits downstream AKT-S6 signaling, suppressing immune cell (T cells, DCs) activation/proliferation and inducing apoptosis in PI3Kδ-dependent B-cell malignancies (CLL)[1] [2][3][4][5] 2. Preclinical significance: - Literature [1]/[5]: Establishes IC-87114 as a tool to study PI3Kδ in immune regulation, with potential in autoimmune/inflammatory diseases. [1][5] - Literature [2]/[4]: Demonstrates efficacy in CLL, including chemosensitization, supporting PI3Kδ as a CLL therapeutic target. [2][4] - Literature [3]: Provides structural basis for PI3Kδ selectivity, guiding development of next-generation PI3Kδ inhibitors. [3] 3. Limitations: - No clinical development data (FDA status); IC-87114 is a preclinical research tool, not a therapeutic candidate. Lack of ADME/toxicity data limits translational potential[1] [2][3][4][5] |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~0.66 mg/mL (~1.7 mM) Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: <1 mg/mL (slightly soluble or insoluble) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 1 mg/mL (2.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 4%DMSO+30%PEG 300+ddH2O: 0.7mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5162 mL | 12.5808 mL | 25.1617 mL | |
| 5 mM | 0.5032 mL | 2.5162 mL | 5.0323 mL | |
| 10 mM | 0.2516 mL | 1.2581 mL | 2.5162 mL |