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| Targets |
PI3Kδ 14 nM (IC50) CYP2C9 2.7 μM (IC50)
IHMT-PI3Kδ-372 targets phosphoinositide 3-kinase delta (PI3Kδ), a class I PI3K isoform that is primarily expressed in leukocytes and plays a critical role in B-cell and T-cell receptor signaling, mast cell activation, and other immune cell functions. By selectively inhibiting PI3Kδ, the compound blocks the production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), thereby inhibiting downstream signaling pathways such as AKT and mTOR that are involved in cell proliferation, survival, and migration. |
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| ln Vitro |
IHMT-PI3Kδ-372 (Compound (S)-18; 0.03-3 μM; 1 hour; Raji cells) therapy suppresses PI3Kδ-mediated AKT T308 phosphorylation in Raji cells with an EC50 value of 67 nM[1]. With an IC50 of 2.7 μM, IHMT-PI3Kδ-372 (compound (S)-18) exhibits moderate suppression of CYP2C9, but no discernible inhibition of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 (IC50s > 10 μM)[1].
IHMT-PI3Kδ-372 demonstrates potent PI3Kδ inhibition with an IC50 of 14 nM in biochemical assays. It shows high selectivity over other class I PI3Ks (56-83 fold) and other protein kinases, minimizing off-target effects. The compound's selectivity profile makes it a valuable tool for studying PI3Kδ-specific functions in immune cells. In vitro studies have characterized its effects on PI3Kδ signaling, cell proliferation, and cytokine production in various immune cell types. |
| ln Vivo |
IHMT-PI3Kδ-372 (Compound (S)-18; 1–5 mg/kg; inhalation; daily; for 28 days) reduces COPD-specific inflammatory patterns and enhances lung function. There is a dose-dependent improvement in lung function measurements such as forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF). Reduced are the unusually high levels of leukocytes, which include neutrophils, lymphocytes, and alveolar macrophages. In a dose-dependent manner, IHMT-PI3Kδ-372 reduces the invasion of inflammatory cells[1]. IHMT-PI3Kδ-372 (compound (S)-18) has a half-life of 2.3 hours, low exposure to 66 ng/mL, and high clearance of 348.5 mL/min/kg in plasma after inhaling a dose of 5 mg/kg in rats. However, lung tissue has a high exposure of 5599 ng/g 6 hours after inhalation[1]. In liver microsomes from humans, rats, and mice, IHMT-PI3Kδ-372 exhibits stability, however in those from dogs and monkeys, it is only moderately stable[1].
IHMT-PI3Kδ-372 (1-5 mg/kg; inhalation; daily; for 28 days) improves lung function and reduces inflammation in preclinical models. These findings suggest potential for treating respiratory and inflammatory diseases. The compound's efficacy in animal models supports further investigation into its therapeutic potential for conditions such as asthma, chronic obstructive pulmonary disease (COPD), and other inflammatory disorders where PI3Kδ plays a pathogenic role. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (cell-free) assay for IHMT-PI3Kδ-372 typically involves a kinase activity assay using recombinant PI3Kδ protein. The kinase is incubated with ATP and a lipid substrate (phosphatidylinositol-4,5-bisphosphate) in the presence of varying concentrations of the compound. The production of phosphatidylinositol-3,4,5-trisphosphate (PIP3) is measured using a radioactive (e.g., 33P-ATP) or fluorescence-based detection method. The IC50 is calculated from the inhibition curve. Selectivity against other PI3K isoforms and kinases is assessed using similar assays.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Raji cells Tested Concentrations: 0.03 μM, 0.1 μM, 0.3 μM, 1 μM, 3 μM Incubation Duration: 1 hour Experimental Results: Inhibited PI3Kδ-mediated AKT T308 phosphorylation in Raji cells with an EC50 value of 67 nM. The in vitro cellular assay for IHMT-PI3Kδ-372 typically uses immune cells such as B cells, T cells, or mast cells. Cells are treated with varying concentrations of the compound, and PI3Kδ signaling is assessed by measuring AKT phosphorylation using Western blot or phospho-specific ELISA. Cell proliferation is measured using BrdU incorporation or CellTiter-Glo assays. Cytokine production is measured by ELISA or multiplex assays. The compound's effects on immune cell activation and function are evaluated in relevant cell-based systems. |
| Animal Protocol |
Animal/Disease Models: SD (Sprague-Dawley) rats (5weeks old) induced with cigarette-smoke and LPS[1]
Doses: 1 mg/kg, 3 mg/kg, and 5 mg/kg Route of Administration: Inhalation; daily; for 28 days Experimental Results: Improved lung function and decreased the inflammatory patterns characteristic of COPD. In vivo animal studies for IHMT-PI3Kδ-372 typically involve models of inflammatory or respiratory diseases. For example, in models of asthma or COPD, the compound is administered via inhalation or other routes at doses of 1-5 mg/kg daily for up to 28 days. Endpoints include lung function measurements, airway inflammation assessment, cytokine levels in bronchoalveolar lavage fluid, and histological analysis of lung tissue. The compound's effects on immune cell populations and activation are also evaluated. |
| ADME/Pharmacokinetics |
Pharmacokinetic data for IHMT-PI3Kδ-372 are not extensively detailed in the available literature. The compound has a molecular weight of 503.50 and a formula of C26H23F2N7O2. It is soluble in DMSO at 50 mg/mL (99.3 mM) and in Ethanol at 50 mg/mL. The compound can be administered via inhalation. Specific ADME parameters such as half-life, bioavailability, and clearance are not reported.
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| Toxicity/Toxicokinetics |
Toxicity data for IHMT-PI3Kδ-372 are not extensively reported. As a research compound, comprehensive toxicological evaluations have not been performed. The compound is intended for laboratory research use only and should be handled with standard safety precautions. Appropriate personal protective equipment should be worn when handling this compound. Consult the Material Safety Data Sheet for specific safety and handling information.
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| References | |
| Additional Infomation |
IHMT-PI3Kδ-372 is a potent and selective PI3Kδ inhibitor (IC50 = 14 nM) with high selectivity over other class I PI3Ks and protein kinases. It has shown efficacy in preclinical models, improving lung function and reducing inflammation. The compound is used to study PI3Kδ signaling in immune cells and its role in inflammatory and autoimmune diseases. IHMT-PI3Kδ-372 is not in clinical trials and has not been approved for therapeutic use. It remains a research tool for studying PI3Kδ biology and inflammation.
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| Molecular Formula |
C26H23F2N7O2
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| Molecular Weight |
503.503331422806
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| Exact Mass |
503.188
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| CAS # |
2429889-62-1
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| PubChem CID |
146635374
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
37
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| Complexity |
891
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1=CC=CC2=C1C(N(C([C@@H](CC)N1C3C(=C(N)N=CN=3)C(C3C=CC(=C(C=3)F)OC)=N1)=N2)C1CC1)=O
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| InChi Key |
HTUBTEAYSCSTIY-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C26H23F2N7O2/c1-3-18(24-32-17-6-4-5-15(27)20(17)26(36)34(24)14-8-9-14)35-25-21(23(29)30-12-31-25)22(33-35)13-7-10-19(37-2)16(28)11-13/h4-7,10-12,14,18H,3,8-9H2,1-2H3,(H2,29,30,31)/t18-/m1/s1
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| Chemical Name |
2-[(1R)-1-[4-amino-3-(3-fluoro-4-methoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]propyl]-3-cyclopropyl-5-fluoroquinazolin-4-one
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 41.67 mg/mL (82.76 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.13 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.08 mg/mL (4.13 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9861 mL | 9.9305 mL | 19.8610 mL | |
| 5 mM | 0.3972 mL | 1.9861 mL | 3.9722 mL | |
| 10 mM | 0.1986 mL | 0.9930 mL | 1.9861 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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