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| Targets |
MSC2360844 (IOA-244) specifically targets the delta isoform of phosphoinositide 3-kinase (PI3Kdelta). PI3Kdelta is primarily expressed in leukocytes and plays a key role in immune cell signaling, proliferation, and survival. The compound binds to an allosteric site on the enzyme, distinct from the ATP-binding pocket, resulting in high selectivity and a reduced off-target toxicity profile.
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| ln Vitro |
Roginolisib (0-10 μM; 1 hour) totally abolishes BCR-induced pAkt in Ramos B cells in a concentration-dependent manner with an IC50 value of 280 nM[1]. With an IC50 of 48 nM, roginolisib suppresses B cell growth in a concentration-dependent manner. Roginolisib inhibits TLR-induced IFNα in human primary cells and BCR- and TCR-mediated responses in lymphocytes [1].
IOA-244 inhibits the in vitro growth of lymphoma cells, and its activity correlates with the expression levels of PIK3CD (the gene encoding p110delta), suggesting cancer cell-intrinsic effects. It inhibits regulatory T cell (Treg) proliferation while having limited antiproliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 during activation favors the differentiation of memory-like, long-lived CD8 T cells known to have increased antitumor capacity. |
| ln Vivo |
In mouse models of SLE, roginolisib (6.6–66 mg/kg; once daily from weeks 2 to 10) improves disease expression [1].
In animal models, IOA-244 showed antitumor activity. In CT26 colorectal and Lewis lung carcinoma models, IOA-244 sensitized tumors to anti-PD-1 treatment, with similar activity in Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. The compound reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and natural killer cells while decreasing suppressive immune cells. It presented no detectable safety concerns in animal studies. |
| Enzyme Assay |
For in vitro PI3Kdelta biochemical assays: Recombinant human PI3Kdelta enzyme (10-50 ng) is incubated with varying concentrations of IOA-244 (0.1-1000 nM) in kinase buffer (20 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM DTT, 0.01% Triton X-100). Add phosphatidylinositol-4,5-bisphosphate (PIP2) substrate (100 uM) and ATP (10 uM). Incubate for 30 minutes at room temperature. Stop the reaction and measure PIP3 production using a homogeneous time-resolved fluorescence (HTRF) or ADP-Glo assay kit. The compound's selectivity should be tested against a large set of kinases, enzymes, and receptors to confirm its unique non-ATP-competitive binding mode.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: B cells Tested Concentrations: 0-10 μM Incubation Duration: 1 hour Experimental Results: Inhibits B cell proliferation in a concentration-dependent manner with an IC50 of 48 nM. For cell-based immune modulation assays: Isolate CD4+ T cells and CD8+ T cells from human peripheral blood mononuclear cells (PBMCs) using magnetic bead separation. Activate T cells with anti-CD3/CD28 antibodies (2 ug/mL each). Treat with IOA-244 (0.1-10 uM) for 3-5 days. Assess Treg proliferation by flow cytometry using FoxP3 staining. Measure CD8+ T cell differentiation by staining for memory markers (CD45RO, CCR7). For cancer cell-intrinsic effects, culture lymphoma cells (e.g., A20, SU-DHL-1) and treat with IOA-244 for 72 hours, then measure viability by CellTiter-Glo and assess PIK3CD expression by western blot or qRT-PCR. |
| Animal Protocol |
Animal/Disease Models: NZB/W F1 female mice [1]
Doses: 6.6, 22 or 66 mg/kg Route of Administration: oral; starting at week 2 after ADV-IFNα administration, one time/day at week 10 Experimental Results: at dose Dramatically diminished incidence and severity of proteinuria in a dependent manner. For syngeneic mouse tumor models: Inoculate 5×10⁵ CT26 colorectal or Lewis lung carcinoma cells subcutaneously into BALB/c mice. When tumors reach approximately 100 mm3, randomly assign mice to treatment groups (n=8-10). Administer IOA-244 orally or intraperitoneally at doses of 10-50 mg/kg daily. For combination therapy, add anti-PD-1 antibody (200 ug/mouse, intraperitoneally every 3 days). Monitor tumor volume using calipers every 2-3 days for 2-3 weeks. At study endpoint, collect tumors and spleens for flow cytometry analysis of immune cell infiltration. |
| Toxicity/Toxicokinetics |
In preclinical studies, IOA-244 presented no detectable safety concerns in animal models. The compound is currently in clinical phase Ib/II investigation for solid and hematologic tumors. Detailed human pharmacokinetic data is not yet publicly available. As a non-ATP-competitive inhibitor, it is expected to have a favorable drug interaction profile and reduced off-target toxicity compared to ATP-competitive PI3Kdelta inhibitors.
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| References | |
| Additional Infomation |
IOA-244 (MSC2360844) is an investigational drug that has entered clinical development. It is currently in phase Ib/II clinical trials for the treatment of solid tumors and hematologic cancers. The compound is not yet approved for clinical use and is intended for research purposes and clinical investigation. This innovative first-in-class PI3Kdelta inhibitor is being evaluated for its ability to modulate T-cell responses and directly inhibit tumor cell growth. No regulatory approval has been granted to date.
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| Molecular Formula |
C26H27FN4O5S
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| Molecular Weight |
526.579788446426
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| Exact Mass |
526.168
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| CAS # |
1305267-37-1
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| Related CAS # |
Roginolisib hemifumarate;1621688-31-0
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| PubChem CID |
66580799
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| Appearance |
White to off-white solid powder
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| LogP |
1.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
37
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| Complexity |
914
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1(C2C(=CC=CC=2C2=C(C(C(N3CCOCC3)=O)=NN2C2C=CC(=CC=2)CN2CCOCC2)C1)F)(=O)=O
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| InChi Key |
NFHSJYKXENYICE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H27FN4O5S/c27-22-3-1-2-20-24-21(17-37(33,34)25(20)22)23(26(32)30-10-14-36-15-11-30)28-31(24)19-6-4-18(5-7-19)16-29-8-12-35-13-9-29/h1-7H,8-17H2
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| Chemical Name |
[6-fluoro-1-[4-(morpholin-4-ylmethyl)phenyl]-5,5-dioxo-4H-thiochromeno[4,3-c]pyrazol-3-yl]-morpholin-4-ylmethanone
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| Synonyms |
MSC 2360844MSC-2360844MSC2360844IOA-244IOA 244IOA244
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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 : ~100 mg/mL (~189.90 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 10 mg/mL (18.99 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 100.0 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: ≥ 10 mg/mL (18.99 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 100.0 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. View More
Solubility in Formulation 3: ≥ 10 mg/mL (18.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8990 mL | 9.4952 mL | 18.9905 mL | |
| 5 mM | 0.3798 mL | 1.8990 mL | 3.7981 mL | |
| 10 mM | 0.1899 mL | 0.9495 mL | 1.8990 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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