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| 5mg |
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| 25mg |
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| 50mg |
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Purity: ≥98%
INCB053914 is a novel, potent, selective, and ATP-competitive small molecule pan-inhibitor of PIM (Proviral Integration site of Moloney murine leukemia virus) kinases with IC50 values of 0.24 nM, 30 nM and 0.12 nM for PIM1, PIM2 and PIM3 respectively in biochemical assays. In cell proliferation assays, INCB053914 is active as a single agent in the majority of cell lines derived from different hematological malignancies, including MM, AML, DLBCL, MCL and T-ALL, with IC50values ranging from 3 - 300 nM. INCB053914 synergizes with a variety of cytotoxic and targeted agents, reducing the viability of a panel of hematological tumor cell lines. In pharmacodynamic assays, INCB053914 inhibits phosphorylation of S6RP, P70S6K, 4E-BP-1 and BAD, known PIM kinase targets. INCB053914 may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.
| ln Vitro |
All multiple myeloma (MM) cell lines examined are inhibited in their ability to proliferate by usansertib; typical GI50 values for AML, MM, DLBCL, MCL, and T-ALL cell lines range from 13.2 nM to 230.0 nM [1]. In MOLM-16 (AML) phosphorylated), Pfeiffer (DLBCL), and KMS-12-PE/BM (MM) cell lines, umansertib (0.1, 0.3, 1, 3, 10, 30, 100, 300, and 1000 nM) inhibits downstream PIM kinase substrates (p70S6K/S6 and 4E-BP1) in a dose-dependent manner [1]. In MOLM-16 and KMS-12-BM cells, PIM kinase-mediated BAD phosphorylation is especially susceptible to Uzansertib inhibition (average IC50 of 4 nM and 27 nM, respectively) [1].
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| ln Vivo |
Uzansertib (25–100 mg/kg; oral; twice daily; for 15 days) dose-dependently suppresses tumor growth in mice expressing KMS-12-BM (MM) or MOLM-16 (AML)[1]. Four hours after injection, uzansertib showed dose-dependent reduction of BAD phosphorylation in comparison to vehicle (IC50=70 nM for MOLM-16 tumors and IC50=145 nM for KMS-12-BM tumors) [1].
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| Animal Protocol |
Animal/Disease Models: Female immunocompromised (severe combined immunodeficiency [SCID]) mice (5-9 weeks old) [1] carrying MOLM-16 (AML) or KMS-12-BM (MM)
Doses: 25, 50 , 75, 100 mg/kg. Doses: Oral; twice a day; for 15 days. Experimental Results: Inhibited tumor growth in mice in a dose-dependent manner. |
| References | |
| Additional Infomation |
Uzansertib is under investigation in clinical trial NCT02587598 (Study of INCB053914 in Subjects With Advanced Malignancies).
Uzansertib is an orally available, small molecule and selective ATP-competitive pan-inhibitor of proviral integration sites for Moloney murine leukemia virus (PIM) kinases, with potential antineoplastic activity. Upon oral administration, uzansertib binds to and inhibits the activities of the three PIM isoforms, PIM1, PIM2 and PIM3. This prevents phosphorylation of their downstream targets and inhibits proliferation in cells that overexpress PIMs. PIMs, constitutively active proto-oncogenic serine/threonine kinases upregulated in various types of cancers, play key roles in tumor cell proliferation and survival. |
| Molecular Formula |
C26H26F3N5O3
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| Molecular Weight |
513.511556148529
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| Exact Mass |
513.198
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| CAS # |
1620012-39-6
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| Related CAS # |
Uzansertib phosphate;2088852-47-3
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| PubChem CID |
90279868
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
37
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| Complexity |
803
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C[C@H]1CN(C[C@H]([C@@H]1O)N)C2=C3CC[C@H](C3=NC=C2NC(=O)C4=NC(=C(C=C4)F)C5=C(C=CC=C5F)F)O
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| InChi Key |
PTORCEYGCGXHDH-OVMXCRKPSA-N
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| InChi Code |
InChI=1S/C26H26F3N5O3/c1-12-10-34(11-17(30)25(12)36)24-13-5-8-20(35)22(13)31-9-19(24)33-26(37)18-7-6-16(29)23(32-18)21-14(27)3-2-4-15(21)28/h2-4,6-7,9,12,17,20,25,35-36H,5,8,10-11,30H2,1H3,(H,33,37)/t12-,17+,20+,25+/m0/s1
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| Chemical Name |
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9474 mL | 9.7369 mL | 19.4738 mL | |
| 5 mM | 0.3895 mL | 1.9474 mL | 3.8948 mL | |
| 10 mM | 0.1947 mL | 0.9737 mL | 1.9474 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.
Structure of INCB053914 and IC50values for the inhibition of PIM isozymes by INCB053914 in biochemical assays.PLoS One.2018 Jun 21;13(6):e0199108. |
INCB053914 inhibits cellular proliferation in hematologic tumor cell lines (A), inhibits phosphorylation of PIM substrates (B), including pBAD (C), and increases PIM2 expression (D) in hematologic tumor cell lines.PLoS One.2018 Jun 21;13(6):e0199108. |
INCB053914 inhibits phosphorylation of PIM substrates and increases PIM2 expression in primary bone marrow (BM) blasts (A), and increases PIM2 expression in PBMCs derived from whole blood samples from patients with AML (B).PLoS One.2018 Jun 21;13(6):e0199108. |
INCB053914 inhibits erythroid colony formation in patients with JAK2 V617F-positive MPNs.PLoS One.2018 Jun 21;13(6):e0199108. |
INCB053914 inhibits the phosphorylation of BAD in mice bearing MOLM-16 (AML) (A) or KMS-12 (MM) tumors (B), and inhibits growth of MOLM-16 (AML) (C) and KMS-12 (MM) (D) tumorsin vivo. Mean INCB053914 plasma concentrations were determined at 2, 4, 8, and 16 hours post oral administration in mice bearing MOLM-16 tumors (E) or KMS-12-BM tumors (F).PLoS One.2018 Jun 21;13(6):e0199108. |
Effects of the selective PI3Kδ inhibitor, INCB050465, on PIM isozyme expression in Pfeiffer DLBCL cells (A). Effects of INCB053914 alone, or in combination with INCB050465, on thein vitroproliferation of Pfeiffer DLBCL cells (B). Effects of INCB053914 alone or in combination with INCB050465 on tumor growth in a DLBCL xenograft model (C); with cytarabine on tumor growth in an AML xenograft model (D); with the JAK1-selective inhibitor, itacitinib, on BAD, STAT3 phosphorylation, and MYC levels (E), and on tumor growth in an INA-6 MM xenograft model (F).PLoS One.2018 Jun 21;13(6):e0199108. |
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