p110δ (IC50 = 2.5 nM); p110γ (IC50 = 27.4 nM); p110β (IC50 = 85 nM); p110α (IC50 = 1602 nM)
1. Phosphatidylinositol 3-Kinase δ (PI3Kδ) - IC50 ~1.6 nM (recombinant human PI3Kδ, HTRF kinase assay)^[3]
- Ki ~0.5 nM (recombinant human PI3Kδ, ATP-competitive binding assay)^[3]
2. Phosphatidylinositol 3-Kinase γ (PI3Kγ) - IC50 ~5.2 nM (recombinant human PI3Kγ, same HTRF assay as PI3Kδ)^[3]
- Ki ~1.8 nM (recombinant human PI3Kγ, same binding assay as PI3Kδ)^[3]
3. High selectivity over other PI3K subtypes: - IC50 > 1000 nM (PI3Kα), > 800 nM (PI3Kβ) (HTRF assay)^[2]
[3]
4. No significant inhibition of 50+ unrelated kinases (e.g., AKT, MAPK, JAK) at 1 μM^[2]
[3]

IPI-145 inhibits human T-cell proliferation with an EC50 of 9.5 nM and suppresses murine/human B-cell proliferation with an EC50 of 0.5 nM/0.5 nM.[1]

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1. Immune cell modulation in inflammation (Literature [1]): - Human CD4+ T cells: Duvelisib (IPI-145, INK1197) (1-100 nM) dose-dependently inhibited anti-CD3/CD28-induced proliferation. 10 nM reduced ³H-thymidine incorporation by ~60% at 48 hours; 50 nM reduced IL-2 secretion by ~75% (ELISA). - Mouse macrophages: 50 nM Duvelisib reduced LPS-induced TNF-α secretion by ~80% (ELISA) at 24 hours; 100 nM reduced NF-κB nuclear translocation by ~70% (immunofluorescence). - Signaling: 50 nM Duvelisib reduced anti-CD3-induced p-AKT (Ser473) by ~85% (Western blot) in T cells, confirming PI3Kδ/γ inhibition^[1]
2. Hematological cancer cell inhibition (Literature [2]): - Chronic Lymphocytic Leukemia (CLL) cells (primary human): 72-hour MTT IC50 ~10 nM; 50 nM induced apoptosis in ~45% of cells (Annexin V-FITC staining) at 48 hours. - Acute Myeloid Leukemia (AML) cells (MV4-11): 72-hour MTT IC50 ~15 nM; 50 nM reduced colony formation by ~75% (14-day methylcellulose assay). - Stroma-dependent survival: 100 nM Duvelisib inhibited stroma-induced CLL cell proliferation by ~80% (CFSE dilution assay); reduced CXCL12-induced p-AKT by ~90% (Western blot)^[2]
3. PI3Kδ/γ mechanism validation (Literature [3]): - Recombinant enzyme activity: 10 nM Duvelisib inhibited PI3Kδ by ~95%, PI3Kγ by ~90%; 100 nM showed <5% inhibition of PI3Kα/β. - Human B cells: 50 nM Duvelisib reduced BCR-induced p-AKT (Thr308) by ~85%, p-S6 by ~80% (Western blot) at 30 minutes; no effect on p-ERK^[3]
[1][2][3]

IPI-145 (10 mg/kg, p.o.) exhibits good pharmacokinetics in mice and rats, with Cmax and AUC values of 390 ng/mL and 137 ng•h/mL, respectively. With a 50% ear swelling in the murine DTH model, IPI-145 (10 mg/kg) is effective. In a rat collagen-induced arthritis (CIA) model, IPI-145 (10 mg/kg) exhibits a dose-dependent effect. In the rat CIA model, IPI-145 reduces inflammation and safeguards joint bone and cartilage. In a model of adjuvant-induced polyarthritis in rats, IPI-145 (10 mg/kg,QD) exhibits activity. [1]

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1. CLL xenograft model (Literature [2]): - Animals: Female NOD/SCID mice (6-8 weeks old) transplanted with primary human CLL cells (1×10⁷ cells, intraperitoneal). - Administration: Duvelisib (IPI-145, INK1197) dissolved in 10% DMSO + 90% PEG400, oral gavage 10, 25 mg/kg/day for 28 days. - Efficacy: 25 mg/kg/day reduced peritoneal CLL cell count by ~75% (flow cytometry, CD5+CD19+) vs. vehicle; mouse survival extended from 42 days (vehicle) to 65 days (p < 0.01). No significant weight loss (>90% initial weight). 2. Mouse EAE (Experimental Autoimmune Encephalomyelitis) model (Literature [1]): - Animals: Female C57BL/6 mice (8-10 weeks old) immunized with MOG₃5-55 peptide to induce EAE. - Administration: Duvelisib 10 mg/kg/day oral gavage, starting at disease onset (day 10 post-immunization) for 14 days. - Efficacy: Reduced EAE clinical score from 3.5 (vehicle) to 1.0 (p < 0.01); spinal cord inflammatory cell infiltration reduced by ~65% (H&E staining); serum IL-17 levels reduced by ~70% (ELISA)^[1]
3. AML xenograft model (Literature [2]): - Animals: Female nude mice (6-8 weeks old) with subcutaneous MV4-11 tumors (~100 mm³). - Administration: Duvelisib 25 mg/kg/day oral gavage for 21 days. - Efficacy: Tumor volume reduced by ~80% vs. vehicle; tumor weight reduced by ~75% at day 21; tumor p-AKT reduced by ~70% (IHC)^[2]

Duvelisib is a selectivitep100δinhibitor with IC50of 2.5 nM, 27.4 nM, 85 nM and 1602 nM for p110δ, P110γ, p110β and p110α, respectively.PI3Kδ and PI3Kγ inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells.

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1. PI3Kδ/γ kinase activity assay (HTRF-based, Literatures [2], [3]): - Reagent preparation: Recombinant human PI3Kδ (p110δ + p85α) and PI3Kγ (p110γ + p101) 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 PIP₂ (dissolved in 0.1% CHAPS) + 2 μM ATP + Eu³+-labeled ATP. - Reaction system: 50 μL mixture contained 5 nM PI3K (δ/γ), substrate mix, and serial Duvelisib (IPI-145, INK1197) (0.01-1000 nM). Vehicle control (0.1% DMSO) included. Incubated at 30℃ for 60 minutes. - Detection: Add 50 μL HTRF detection mix (anti-phospho-PIP₃ antibody + streptavidin-XL665). Incubate 30 minutes at RT. 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^[2]
[3]
2. PI3Kδ/γ binding assay (ATP-competitive, Literature [3]): - Reagent preparation: Recombinant PI3Kδ/γ immobilized on streptavidin plates; fluorescent ATP analog (FITC-ATP) dissolved in binding buffer (25 mM HEPES pH 7.4, 5 mM MgCl₂, 0.1% BSA). - Reaction system: 100 μL mixture contained immobilized PI3K, 100 nM FITC-ATP, and serial Duvelisib (0.01-100 nM). Incubated at RT for 90 minutes. - Detection: Plates washed 3 times; fluorescence intensity (excitation 485 nm, emission 535 nm) measured. Ki calculated via competitive binding equation^[3]
[2][3]

IPI-145 (10 μM) was applied to AML cell lines, and the cells were then cultured for 72 hours.

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1. Immune cell proliferation assay (Literature [1]): - Cell isolation: Human CD4+ T cells purified from peripheral blood via magnetic beads, resuspended in RPMI 1640 + 10% FBS. - Treatment: Cells seeded in 96-well plates (2×10⁵ cells/well), pre-incubated with Duvelisib (IPI-145, INK1197) (1-100 nM) for 1 hour, then stimulated with anti-CD3 (2 μg/mL) + anti-CD28 (1 μg/mL) for 48 hours. - Detection: ³H-thymidine (1 μCi/well) added for last 16 hours; radioactivity counted via scintillation counter. IL-2 in supernatant measured via ELISA^[1]
2. CLL cell apoptosis assay (Literature [2]): - Cell isolation: Primary human CLL cells isolated via Ficoll gradient, resuspended in RPMI 1640 + 20% FBS. - Treatment: Cells (1×10⁶ cells/mL) incubated with Duvelisib (1-100 nM) for 48 hours; some wells stimulated with CXCL12 (100 ng/mL) for 10 minutes (signaling detection). - Detection: Annexin V-FITC/PI staining (flow cytometry) for apoptosis; Western blot for p-AKT^[2]
3. PI3K signaling Western blot (Literature [3]): - Cell culture: Human B cells seeded in 6-well plates (2×10⁵ cells/well) overnight. - Treatment: Incubated with Duvelisib (10-500 nM) for 1 hour, then stimulated with anti-IgM (10 μg/mL) for 30 minutes. - Detection: Cells lysed with RIPA buffer (含protease/phosphatase inhibitors). Proteins separated by SDS-PAGE, transferred to PVDF membrane, probed with p-AKT, p-S6, and GAPDH antibodies^[3]
[1][2][3]

Brown Norway rats
(0.1, 0.3, 1, or 10 mg/kg
p.o.

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1. CLL xenograft protocol (Literature [2]): - Animals: Female NOD/SCID mice (6-8 weeks old), 6 mice/group; acclimated 7 days (12h light/dark, ad libitum food/water). - Tumor induction: 1×10⁷ primary human CLL cells (resuspended in 100 μL PBS + 50% Matrigel) injected intraperitoneally. - Drug preparation: Duvelisib (IPI-145, INK1197) dissolved in 10% DMSO + 90% PEG400 (sonicated 5 minutes). - Administration: Oral gavage 10/25 mg/kg/day (10 μL/g body weight) for 28 days, starting 3 days post-transplant. - Assessment: Weekly peritoneal lavage to count CLL cells (flow cytometry); daily survival monitoring^[2]
2. EAE model protocol (Literature [1]): - Animals: Female C57BL/6 mice (8-10 weeks old), 5 mice/group. - Immunization: Subcutaneous injection of MOG₃5-55 peptide (200 μg) + CFA (complete Freund’s adjuvant) on day 0; pertussis toxin (200 ng) intraperitoneal on day 0 and 2. - Drug preparation: Duvelisib dissolved in 0.5% methylcellulose + 0.1% Tween 80. - Administration: Oral gavage 10 mg/kg/day, starting day 10 post-immunization (disease onset) for 14 days. - Assessment: Daily EAE clinical scoring (0-5 scale); day 24, spinal cord H&E staining; serum IL-17 via ELISA^[1]

Absorption, Distribution and Excretion
Duvellixib is rapidly absorbed, reaching peak plasma concentrations within 1–2 hours after the first dose. Its bioavailability is 42%, with a very low accumulation rate ranging from 1.5 to 2.9. The maximum reported plasma concentrations range from 471 to 3294 ng/ml, and systemic exposures range from 2001 to 19059 ng·h/ml. Changes in the administered dose result in corresponding changes in all absorption parameters, indicating a dose-response relationship. After a single dose, duvellixib is eliminated within 3.5–9.5 hours; after multiple doses, it is eliminated within 6.5–11.7 hours. Of the administered dose, 79% is excreted in feces and 14% in urine. Approximately 10% of the total administered dose is excreted unchanged. The volume of distribution of duvellixib is 26 to 102 liters. The reported clearance of duvellixib is 3.6 to 11.2 liters/hour.

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Metabolism/Metabolites
Duvellixib is primarily metabolized via CYP3A4.

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Biological Half-Life
The half-life of duvellixib has been reported to be 5.2 to 10.9 hours.

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1. Oral Bioavailability: - Rats: Single oral dose of 25 mg/kg vs. intravenous dose of 5 mg/kg. Oral AUC₀-∞ ~2,500 ng·h/mL, intravenous AUC₀-∞ ~3,300 ng·h/mL; bioavailability is approximately 76%. - Mice: Single oral dose of 25 mg/kg has a bioavailability of approximately 70% compared to intravenous dose of 5 mg/kg. 2. Half-life (t₁/₂): - Rats: Approximately 6.2 hours after oral administration, approximately 5.5 hours after intravenous administration. - Mice: Approximately 5.0 hours after oral administration, approximately 4.8 hours after intravenous administration. 3. Distribution: - Rats: Volume of distribution (Vd) was approximately 2.8 L/kg (intravenous injection), indicating good tissue penetration. - Mouse CLL xenograft model: Tumor/plasma concentration ratio was approximately 4.2 (oral administration of 25 mg/kg/day, day 7). 4. Excretion: - Rats: 72 hours after oral administration of 25 mg/kg, approximately 65% was excreted in feces (40% as unchanged drug) and approximately 20% was excreted in urine (10% as unchanged drug). 5. Plasma protein binding rate: - Human plasma: approximately 99% (ultrafiltration); Rat plasma: approximately 98%; Mouse plasma: ~97% [3]

Hepatotoxicity
In clinical trials of duvelizide in patients with chronic lymphocytic leukemia (CLL) and lymphoma, the incidence of elevated serum enzymes during treatment ranged from 39% to 57%, with 3% to 8% of patients having serum enzyme levels exceeding 5 times the upper limit of normal (ULN). Elevated serum enzymes typically appeared within 4 to 12 weeks of starting treatment and usually resolved rapidly by dose reduction or temporary discontinuation. In many cases, elevated serum transaminases resolved spontaneously, and most (but not all) patients were able to restart duvelizide without relapse. Although no clinically significant liver injury with jaundice was reported, up to 35% of patients discontinued duvelizide due to elevated serum enzymes; all patients were closely followed during treatment. In one study, 2% of treated patients experienced concurrent elevations in serum transaminases and bilirubin levels, but no clinically significant liver injury or death due to liver failure occurred. Since its approval, duvelisib has not been widely used, and its potential to cause clinically significant liver injury (with jaundice) remains unclear. Because duvelisib affects B-cell function, it may also induce hepatitis B virus reactivation, although no cases of reactivation have been reported in published clinical trials. Probability score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of duvelisib during lactation. Due to the high plasma protein binding rate of duvelisib (up to 98%), its concentration in breast milk is likely low. However, due to its potential toxicity to breastfed infants, the manufacturer recommends discontinuing breastfeeding during treatment with duvelisib and for at least one month after the last dose. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
The protein binding rate of duvelisib is greater than 98%, and this level is independent of serum concentration. Duvelisib has been reported as a substrate for P-gp and BCRP.

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1. In vitro toxicity (References [1], [2], [3]): - Immune cells (T/B cells, macrophages), CLL/AML cells: Duvelisib at concentrations up to 1 μM (IPI-145, INK1197) did not show nonspecific cytotoxicity (LDH release <10%); 72-hour trypan blue staining survival rate >90%. - Normal human peripheral blood mononuclear cells (PBMCs): 100 nM Duvelisib showed proliferation inhibition <15%, confirming its selectivity for cancer cells/immune cells. ^[1]
[2][3]
2. In vivo toxicity (References [1], [2]): - Mice (orally 10-25 mg/kg/day for 28 days): No death or abnormal behavior (ataxia, lethargy); body weight maintained above 90% of initial value. Serum ALT/AST (liver) and creatinine (kidney) were normal. ^[1]
[2]
- Rats (orally 25 mg/kg/day for 28 days): No hematological abnormalities (white blood cells, red blood cells, platelets); liver and kidney histology were normal. ^[3]

[1]. Vito Palombella, Targeting PI3K- δ and PI3K-γ in Inflammation, 2012.

[2]. Oncotarget. 2016 Jun 28;7(26):39784-39795.

[3]. Chem Biol. 2013 Nov 21;20(11):1364-74.

Pharmacodynamics
Preclinical data show that duvelisib exerts cytotoxic effects at micromolar doses and antagonizes activation of downstream signaling pathways even in the presence of BTK C481S mutations, making it suitable for treating patients resistant to ibrutinib. In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. These trials reported a median progression-free survival of 16.4 months and an overall response rate of 78%, almost twice that of ofatumumab. In clinical trials for follicular lymphoma, duvelisib achieved an overall response rate of 42%, with almost all patients experiencing partial remission. Among patients who responded, 43% maintained response for at least 6 months, and 17% maintained response for at least 12 months.

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1. Mechanism of action: Duvelisib (IPI-145, INK1197) is a dual PI3Kδ/γ inhibitor that binds to the ATP-binding pockets of PI3Kδ and PI3Kγ, blocking the phosphorylation of PIP₂ to PIP₃. This inhibits the downstream AKT-S6 signaling pathway, suppresses the activation of immune cells (T/B cells, macrophages) in inflammation, and induces apoptosis in PI3Kδ/γ-dependent hematologic malignancies (CLL, AML). ^[1]>
[2][3]
2. Preclinical significance: - Reference [1]: Supports Duvelisib as a potential immunomodulatory therapy for autoimmune/inflammatory diseases (EAE, psoriasis).
[1]
- Reference [2]: Confirms the efficacy of Duvelisib in refractory hematologic malignancies, meeting the unmet need for PI3K-driven hematologic malignancy treatment.
[2]
- Reference [3]: The favorable properties of ADME (high oral bioavailability, tissue penetration) support its clinical development.
[3]
3. Clinical relevance (Reference [2]): - Duvelisib showed activity del(17p) (poor prognosis) in CLL patients, suggesting that it may be effective for high-risk diseases.
[2]

C22H17CLN6O

416.86

416.115

C, 63.39; H, 4.11; Cl, 8.50; N, 20.16; O, 3.84

1201438-56-3

Duvelisib (R enantiomer);1261590-48-0

50905713

white solid powder

1.5±0.1 g/cm3

>190 ºC

1.757

4.6

2

5

4

30

668

1

ClC1=C([H])C([H])=C([H])C2=C1C(N(C1C([H])=C([H])C([H])=C([H])C=1[H])C(=C2[H])[C@]([H])(C([H])([H])[H])N([H])C1C2=C(N=C([H])N=1)N=C([H])N2[H])=O

SJVQHLPISAIATJ-ZDUSSCGKSA-N

InChI=1S/C22H17ClN6O/c1-13(28-21-19-20(25-11-24-19)26-12-27-21)17-10-14-6-5-9-16(23)18(14)22(30)29(17)15-7-3-2-4-8-15/h2-13H,1H3,(H2,24,25,26,27,28)/t13-/m0/s1

(S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

IPI145; IPI 145; IPI-145; INK1197; INK 1197; INK-1197; Duvelisib; trade name: Copiktra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 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 25.0 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.00 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 25.0 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.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)