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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 investigated multiple myeloma (MM) cell lines are inhibited in their proliferation by umansertib phosphate; typical GI50 values for AML, MM, DLBCL, MCL, and T-ALL cell lines range from 13.2 nM to 230.0 nM [1]. The phosphorylation of downstream PIM kinase substrates (p70S6K/S6 and 4E-BP1) is inhibited by umansertib phosphate (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) in a dose-dependent manner in MOLM-16 alteration. AML), KMS-12-PE/BM (MM), and Pfeiffer (DLBCL) cell lines [1]. In MOLM-16 and KMS-12-BM cells, PIM kinase-mediated BAD phosphorylation is especially susceptible to Uzansertib phosphate inhibition (mean IC50 of 4 nM and 27 nM, respectively) [1].
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| ln Vivo |
In mice with MOLM-16 (AML) or KMS-12-BM (MM) tumors, usansertib phosphate (25–100 mg/kg; oral; twice daily; for 15 days) suppresses tumor growth in a dose-dependent manner[1]. Four hours after injection, uzansertib phosphate 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 |
| Molecular Formula |
C26H29F3N5O7P
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| Molecular Weight |
611.5067
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| Exact Mass |
611.175
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| CAS # |
2088852-47-3
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| Related CAS # |
Uzansertib;1620012-39-6
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| PubChem CID |
126673672
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
42
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| Complexity |
853
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| Defined Atom Stereocenter Count |
4
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| SMILES |
P(=O)(O[H])(O[H])O[H].FC1C([H])=C([H])C(C(N([H])C2=C([H])N=C3[C@@]([H])(C([H])([H])C([H])([H])C3=C2N2C([H])([H])[C@]([H])([C@@]([H])([C@@]([H])(C([H])([H])[H])C2([H])[H])O[H])N([H])[H])O[H])=O)=NC=1C1C(=C([H])C([H])=C([H])C=1F)F
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| InChi Key |
CYYVLFVRZDZABX-SEDYQSMDSA-N
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| InChi Code |
InChI=1S/C26H26F3N5O3.H3O4P/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;1-5(2,3)4/h2-4,6-7,9,12,17,20,25,35-36H,5,8,10-11,30H2,1H3,(H,33,37);(H3,1,2,3,4)/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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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) |
Solubility in Formulation 1: ≥ 1.8 mg/mL (2.94 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 18.0 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: ≥ 1.8 mg/mL (2.94 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 18.0 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: ≥ 1.8 mg/mL (2.94 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 | 1.6353 mL | 8.1765 mL | 16.3530 mL | |
| 5 mM | 0.3271 mL | 1.6353 mL | 3.2706 mL | |
| 10 mM | 0.1635 mL | 0.8176 mL | 1.6353 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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