| Size | Price | Stock | Qty |
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Purity: ≥98%
Ilorasertib (also known as ABT-348) is a potent, novel, orally bioavailable and ATP-competitive multi-kinase inhibitor with IC50s for inhibiting binding Aurora B (7 nM), C (1 nM), and A (120 nM), and also inhibits RET tyrosine kinase, PDGFRβ, and Flt1 with IC50s of 7 nM, 3 nM and 32 nM. ABT 348 was assessed and found to be efficacious in representative solid tumor (HT1080 and MiaPaCa, tumor stasis) and hematological malignancy (RS4;11, regression) xenografts due to its distinct spectrum of activity. The rationale behind evaluating ABT-348 clinically as a therapeutic agent for cancer treatment is provided by these findings.
| Targets |
Aurora C (IC50 = 1 nM); Aurora B (IC50 = 7 nM); Aurora B (Y156H) (IC50 = 12 nM); Aurora A (IC50 = 120 nM); PDGFRα (IC50 = 11 nM); PDGFRβ (IC50 = 13 nM); VEGFR1 (IC50 = 1 nM); VEGFR2 (IC50 = 2 nM); VEGFR3 (IC50 = 43 nM); FLT3 (IC50 = 1 nM); CSF-1R (IC50 = 3 nM); c-KIT (IC50 = 20 nM)
Aurora A (IC₅₀ = 120 nM in enzyme assay; 189 nM in cellular autophosphorylation assay) Aurora B (IC₅₀ = 7 nM in enzyme assay; 13–21 nM in cellular assays) Aurora C (IC₅₀ = 1 nM in enzyme assay; 13 nM in cellular assay) VEGFR1 (IC₅₀ = 1 nM in enzyme assay; 0.3 nM in cellular assay) VEGFR2 (IC₅₀ = 2 nM in enzyme assay; 5 nM in cellular assay) VEGFR3 (IC₅₀ = 43 nM in enzyme assay; 2 nM in cellular assay) FLT-3 (IC₅₀ = 1 nM in enzyme assay; 2 nM in cellular assay) CSF-1R (IC₅₀ = 3 nM in enzyme assay; 3 nM in cellular assay) KIT (IC₅₀ = 20 nM in enzyme assay; 45 nM in cellular assay) PDGFR-α (IC₅₀ = 11 nM in enzyme assay; 16 nM in cellular assay) PDGFR-β (IC₅₀ = 13 nM in enzyme assay; 11 nM in cellular assay) Src family kinases (potent inhibition, no specific IC₅₀ given) Mutant Aurora B (Y156H) (IC₅₀ = 12 nM in enzyme assay) |
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| ln Vitro |
Ilorasertib (0, 3, 10, 30 nM; 24 h) causes an increase in H1299, H460 cell extent and number that is concentration-dependent[2].
Ilorasertib (1-1000 nM) demonstrates antiproliferative properties [2]. ABT-348 inhibits proliferation of leukemia, lymphoma, and solid tumor cell lines with IC₅₀ values ranging from 0.3 to 103 nM. It induces polyploidy in NSCLC cell lines (H1299 and H460) with EC₅₀ values of approximately 5 and 10 nM. It inhibits VEGF-stimulated HUVEC proliferation with IC₅₀ ≤ 0.3 nM, but has minimal effect on non-proliferating HUVEC (IC₅₀ > 1000 nM). It inhibits colony formation of solid tumor cell lines in 7–10 day assays. It retains activity against multidrug-resistant HCT-15 colorectal cancer cells. It inhibits BCR-ABL wild-type and T315I mutant cells with IC₅₀ values of 47 and 260 nM, respectively. |
| ln Vivo |
Ilorasertib (6.25, 12.5, 25 mg/kg; p.o.) demonstrates anti-tumor activity in SCID mice bearing MV-4-11 tumors, with TGI values of 80%, 86%, and 94% at 6.25, 12.5, and 25 mg/kg, respectively[1].
Ilorasertib (6.25, 12.5, 25 mg/kg; p.o.) demonstrates antitumor activity in SCID mice bearing SKM-1 tumors, with TGI values of 38%, 59%, and 80% at 6.25, 12.5, and 25 mg/kg, respectively[1]. Ilorasertib (0, 3.75, 7.5, 15 mg/kg; i.p.) inhibits the phosphorylation of histone H3 in blood-borne tumor cells between 4 and 8 hours[2]. Ilorasertib (0.2 mg/kg; i.v.) exhibits anti-VEGF activity in mice[2]. Ilorasertib (20 mg/kg; p.o.;once weekly for 3 weeks) exhibits antitumor activity in mouse[2]. ABT-348 inhibits tumor growth in HT1080 fibrosarcoma xenografts with dose-dependent efficacy when administered three times weekly (10 and 20 mg/kg). It induces tumor regression in pancreatic carcinoma (MiaPaCa) and leukemia (RS4;11) xenografts with once-weekly dosing (20 mg/kg). It prolongs survival in a disseminated leukemia engraftment model (RS4;11) with intermittent treatment via osmotic minipumps. It inhibits histone H3 phosphorylation in circulating tumor cells and solid tumors in a dose- and time-dependent manner. It blocks VEGF-mediated uterine edema with ED₅₀ ≈ 0.2 mg/kg. It increases plasma PLGF levels in tumor-bearing mice. It reduces tumor vascular permeability (Ktrans) in a rat glioma model as measured by DCE-MRI. |
| Enzyme Assay |
Kinase inhibitory activity was assessed using recombinant kinase domains expressed in baculovirus.
Tyrosine kinase and Aurora kinase assays were performed in a homogeneous time-resolved fluorescence format using a biotinylated peptide substrate, ATP, a europium-cryptate-labeled antibody, and streptavidin-APC. Ser/Thr kinase assays used a radioactive format with ³³P-ATP and biotinylated peptide captured on streptavidin-coated flash plates. IC₅₀ values were determined using nonlinear regression analysis of concentration-response data. |
| Cell Assay |
Cell Line: H1299, H460 cells
Concentration: 0, 3, 10, 30 nM Incubation Time: 24 h Result: Induced a concentration-dependent increase in the extent and number of cells exhibiting polyploidy with EC50S of 5, 10 nM for H1299, H460 cells, respectively. For proliferation assays, carcinoma cells were plated and treated with compound for 72 hours, followed by viability measurement using alamarBlue or Cell TiterGlo. Leukemia cells were plated at higher density and treated similarly. Colony formation assays involved seeding 500 cells/well, treating with compound for 7–10 days, then fixing and staining with crystal violet. Polyploidy induction was assessed by flow cytometry after 24-hour compound exposure. Histone H3 phosphorylation was measured by ELISA or Western blot in nocodazole-arrested cells. Receptor phosphorylation assays used engineered cell lines stimulated with ligands, followed by ELISA or Western blot analysis. |
| Animal Protocol |
Female SCID/beige mice[2]
25 mg/kg Subcutaneous minipump; 24 h For flank xenograft models, tumor cells were mixed with Matrigel and inoculated into female SCID/beige mice. Treatment began when tumors reached ~0.4–0.5 cm³. ABT-348 was administered intraperitoneally or orally in a vehicle containing ethanol, Tween 80, PEG 400, and hydroxypropyl methylcellulose. Dosing schedules included once weekly (20 mg/kg) or three times weekly (10–20 mg/kg). For leukemia engraftment, NOD/SCID mice were irradiated, inoculated with RS4;11 cells, and treated via osmotic minipumps implanted subcutaneously. Uterine edema assay involved pretreating mice with compound intravenously, followed by estradiol challenge, and uterine weight measurement after 3 hours. DCE-MRI studies in rat glioma models assessed changes in tumor perfusion after ABT-348 treatment. |
| ADME/Pharmacokinetics |
ABT-348 exhibits a high plasma protein binding rate (>99%) in mouse blood. Plasma concentrations were determined using liquid chromatography-mass spectrometry (LC-MS) with methanol precipitated by acidification. In vivo, the concentration required to inhibit histone H3 phosphorylation by 50% is approximately 1–2 μM in solid tumors and approximately 3.2 μM in circulating leukemia cells.
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| Toxicity/Toxicokinetics |
In the HT1080 xenograft model, a dose of 20 mg/kg three times a week resulted in increased mortality and was considered intolerable. A dose of 10 mg/kg three times a week resulted in weight loss but did not increase mortality and was considered reasonably tolerable. In pancreatic cancer and leukemia models, a once-weekly (20 mg/kg) dosing regimen was well tolerated, with no significant weight loss observed.
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| References |
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| Additional Infomation |
Ilorasertib has been used in clinical trials for the treatment of myelodysplastic syndromes, solid tumors, advanced cancers, and acute myeloid leukemia. Ilorasertib is an orally bioavailable adenosine triphosphate analog that inhibits Aurora kinase, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), exhibiting potential antitumor activity. After administration, ilorasertib selectively binds to and inhibits Aurora kinases A, B, and C, potentially disrupting mitotic spindle assembly and chromosome segregation, and inhibiting cell division and proliferation in Aurora kinase-overexpressing tumor cells. Furthermore, ilorasertib selectively binds to and inhibits VEGFR and PDGFR, thereby inhibiting angiogenesis and tumor cell proliferation in VEGFR/PDGFR-overexpressing tumor cells. The drug also inhibits Src family cytoplasmic tyrosine kinases. Aurora kinases A, B, and C are serine/threonine kinases that play important roles in mitotic checkpoint regulation and are overexpressed in various tumor cell types. VEGFR and PDGFR are both members of the receptor tyrosine kinase family and are upregulated in various tumor cell types. ABT-348 is a multi-target kinase inhibitor designed to simultaneously inhibit Aurora kinases, VEGFR/PDGFR family kinases, and Src family kinases. It is not a substrate for MDR1 or breast cancer resistance protein transporters, and therefore remains active in multidrug resistance models. Clinical monitoring using biomarkers such as histone H3 phosphorylation and PLGF levels is recommended. This compound has shown efficacy in both solid tumor and hematologic malignancy models, supporting its potential for clinical evaluation in cancer treatment.
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| Molecular Formula |
C25H21N6O2FS
|
|---|---|
| Molecular Weight |
488.537
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| Exact Mass |
488.143
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| Elemental Analysis |
C, 61.46; H, 4.33; F, 3.89; N, 17.20; O, 6.55; S, 6.56
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| CAS # |
1227939-82-3
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| Related CAS # |
Ilorasertib hydrochloride;1847485-91-9
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| PubChem CID |
46207586
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| Appearance |
Off-white to brown solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
675.7±55.0 °C at 760 mmHg
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| Flash Point |
362.4±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.735
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| LogP |
5.5
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
713
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NC1=CC=CC(F)=C1)NC2=CC=C(C3=CSC4=C3C(N)=NC=C4C5=CN(CCO)N=C5)C=C2
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| InChi Key |
WPHKIQPVPYJNAX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H21FN6O2S/c26-17-2-1-3-19(10-17)31-25(34)30-18-6-4-15(5-7-18)21-14-35-23-20(12-28-24(27)22(21)23)16-11-29-32(13-16)8-9-33/h1-7,10-14,33H,8-9H2,(H2,27,28)(H2,30,31,34)
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| Chemical Name |
1-[4-[4-amino-7-[1-(2-hydroxyethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]-3-(3-fluorophenyl)urea
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| Synonyms |
Abbott-968660; Ilorasertib; ABT348; ABT-348; ABT 348; Abbott 968660
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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: ~41.7 mg/mL (~85.3 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.26 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 (4.26 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0469 mL | 10.2346 mL | 20.4692 mL | |
| 5 mM | 0.4094 mL | 2.0469 mL | 4.0938 mL | |
| 10 mM | 0.2047 mL | 1.0235 mL | 2.0469 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02540876 | Completed | Other: Laboratory Biomarker Analysis Drug: Ilorasertib |
Metastatic Malignant Neoplasm Solid Neoplasm |
University of Chicago | September 8, 2015 | Phase 1 |
| NCT01110473 | Completed | Drug: ABT-348 and azacitidine Drug: ABT-348 |
Myelodysplasia Chronic Myelogenous Leukemia |
AbbVie (prior sponsor, Abbott) |
April 2010 | Phase 1 |
| NCT01110486 | Recruiting | Drug: ABT-348 Drug: ABT-348 and carboplatin |
Advanced Solid Tumors | AbbVie (prior sponsor, Abbott) |
March 2010 | Phase 1 |
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