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Purity: ≥98%
Padnarsertib (KPT-9274; KPT9274; PAK4-IN-1) is a potent, selective, orally bioavailable small molecule, non-competitive dual inhibitor of PAK4/NAMPT inhibitor with anticancer activity. KPT-9274 disrupts the PAK4/NAMPT signaling pathway, which may lead to the reduction of G2-M transit and induction of apoptosis as well as decrease in cell invasion and migration in several human RCC cell lines. Inhibition of the PAK4 signaling pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in a mouse model and is under a phase I clinical trial for solid tumors and lymphomas.
| ln Vitro |
Padnarsertib inhibits the PAK4/β-catenin pathway, which results in NAD depletion and reduces the capacity of many RCC cell lines to invade, migrate, and remain viable. Padnarsertib has an IC50 of about 120 nM, according to a cell-free enzymatic experiment that used recombinant NAMPT to inhibit NAMPT. In RCC cell lines, padnarsertib can cause apoptosis and impair G2-M trafficking [2].
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| ln Vivo |
Padnarsertib and sunitinib demonstrated similar effectiveness in inhibiting the growth of xenografts. Padnarsertib does not appear to be toxic in vivo and has minimal effect on normal human RPTEC [2]. Padnarsertib (oral; 100 mg/kg or 200 mg/kg; twice daily for 14 days) resulted in decreased xenograft growth in animal models without significantly affecting animal body weight. The concentrations in mouse plasma and tumors were found to be 10757 ng/mL and 10647 ng/mL, respectively, at the conclusion of the 8-hour experiment [3].
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| Animal Protocol |
Animal/Disease Models: Mice[1]
Doses: 100mg/kg or 200 mg/kg Route of Administration: Oral administration; 100mg/kg or 200 mg/kg; twice a day; 14 days Experimental Results: demonstrated a significant decrease of xenograft growth in KPT-9274 treated mouse. |
| References | |
| Additional Infomation |
Padnarsertib is an orally bioavailable inhibitor of both the serine/threonine kinase P21-activated kinase 4 (PAK4) and the nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT; NAMPRTase), with potential antineoplastic activity. Upon administration, padnarsertib allosterically binds to, destabilizes and causes degradation of PAK4. This inhibits PAK4-mediated signaling, induces cell death in, and inhibits the proliferation of PAK4-overexpressing tumor cells. In addition, padnarsertib binds to and inhibits the activity of NAMPT. This depletes cellular NAD and inhibits NAD-dependent enzymes, both of which are needed for rapid cell proliferation; this results in tumor cell death in NAMPT-overexpressing cancer cells. PAK4, a serine/threonine kinase and member of the PAK family of proteins upregulated in various cancer cell types, regulates cell motility, proliferation and survival. NAMPT, an enzyme that is responsible for maintaining the intracellular NAD pool, plays a key role in the regulation of cellular metabolism and has cytokine-like activities. NAMPT is often overexpressed in a variety of cancers and metabolic disorders and tumor cells rely on NAMPT activity for their NAD supply.
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| Molecular Formula |
C35H29F3N4O3
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|---|---|---|
| Molecular Weight |
610.63
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| Exact Mass |
610.219
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| CAS # |
1643913-93-2
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| Related CAS # |
1643913-93-2;Padnarsertib HCl;
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| PubChem CID |
117779453
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| Appearance |
White to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
857.5±65.0 °C at 760 mmHg
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| Flash Point |
472.4±34.3 °C
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| Vapour Pressure |
0.0±3.2 mmHg at 25°C
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| Index of Refraction |
1.677
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| LogP |
4.74
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
45
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| Complexity |
1040
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1CN(CCC1(F)F)C(=O)C2=CC=C(C=C2)C3=CC(=C4C(=C3)C=C(O4)CNC(=O)/C=C/C5=CN=C(C=C5)N)C6=CC=C(C=C6)F
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| InChi Key |
MRFOPLWJZULAQD-SWGQDTFXSA-N
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| InChi Code |
InChI=1S/C35H29F3N4O3/c36-28-9-7-24(8-10-28)30-19-26(23-3-5-25(6-4-23)34(44)42-15-13-35(37,38)14-16-42)17-27-18-29(45-33(27)30)21-41-32(43)12-2-22-1-11-31(39)40-20-22/h1-12,17-20H,13-16,21H2,(H2,39,40)(H,41,43)/b12-2+
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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) |
Solubility in Formulation 1: 2.08 mg/mL (3.41 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (3.41 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.41 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 | 1.6377 mL | 8.1883 mL | 16.3765 mL | |
| 5 mM | 0.3275 mL | 1.6377 mL | 3.2753 mL | |
| 10 mM | 0.1638 mL | 0.8188 mL | 1.6377 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.
KPT-9274 inhibits NAMPT and PAK4 and associated signaling pathways in RCC cells.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
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 KPT-9274 preferentially attenuates RCC cell viability and decreases RCC invasion and migration.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
KPT-9274 decreases G2/M transit and causes apoptosis preferentially in RCC cells.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
 KPT-9274 shows specificity for attenuation of PAK4 targets preferentially in RCC cells.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
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 KPT-9274 shows specificity for attenuation of NAD biosynthesis targets preferentially in RCC cells.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
 KPT-9274 attenuates xenograft growthin vivowith minimal toxicity and shows the expected on-target effects.Mol Cancer Ther.2016 Sep;15(9):2119-29. |
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