| Identification | Back Directory | [Name]
KPT-9294 | [CAS]
1643913-93-2 | [Synonyms]
CS-1746
KPT-9294
PAK4-IN-1
PAK4-IN-1(KPT9274)
KPT 9274;KPT9274;KPT-9274
(2E)-3-(6-Amino-3-pyridinyl)-N-[[5-[4-[(4,4-difluoro-1-piperidinyl)carbonyl]phenyl]-7-(4-fluorophenyl)-2-benzofuranyl]methyl]-2-propenamide
2-Propenamide, 3-(6-amino-3-pyridinyl)-N-[[5-[4-[(4,4-difluoro-1-piperidinyl)carbonyl]phenyl]-7-(4-fluorophenyl)-2-benzofuranyl]methyl]-, (2E)- | [Molecular Formula]
C35H29F3N4O3 | [MDL Number]
MFCD30207881 | [MOL File]
1643913-93-2.mol | [Molecular Weight]
610.62 |
| Chemical Properties | Back Directory | [Boiling point ]
857.5±65.0 °C(Predicted) | [density ]
1.39±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
≥22.45 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH | [form ]
solid | [pka]
12.96±0.46(Predicted) | [color ]
White to light yellow |
| Hazard Information | Back Directory | [Uses]
Padnarsertib (KPT-9274) is an orally bioavailable, dual PAK4/Nicotinamide phosphoribosyltransferase (Nampt) inhibitor, with IC50s of <100 nM and 120 nM, respectively[1][2][3]. | [Biological Activity]
kpt-9274 is a selective and orally bioavailable allosteric inhibitor of pak4 [1][2][3].p21 protein (cdc42/rac)-activated kinase 4 (pak4) is a serine/threonine-protein kinase and a member of the pak family of proteins which are rac1 and cdc42 effectors. pak4 is a mediator of filopodia formation and stabilizes β-catenin transcriptional activity, and is involved in disease progression for several solid tumors [1][2][3].kpt-9274 is a selective and orally bioavailable pak4 inhibitor. in mda-mb-468 cells, kpt-9274 showed anti-tumor activity with ic50 value of 0.12 μm. kpt-9274 reduced pak4 protein and the key downstream effectors of cell cycle (β-catenin, cyclin d1), cell migration (cofilin), autophagy (ampk) and apoptosis (caspase and parp cleavage) [1]. in rcc cells, kpt-9274 dose-dependently inhibited cell viability [2]. in aml cell lines, kpt-9274 (1 nm-10 μm) inhibited cell proliferation in a dose-and time- dependent way and reduced protein and mrna expression of pak4 [3].in mice inoculated with mda-mb-231 or mda-mb-468 cells, kpt-9274 were given orally once daily (5 or 7 days/week) without major toxicity. kpt-9274 induced a maximum tgi of ~55% and ~70% in mda-mb-231 and mda-mb-468 mice, respectively [1]. in subcutaneous xenograft mouse models, kpt-9274 inhibited rcc growth [2]. in human aml leukemia xenograft model, kpt-9274 (150 mg/kg) significantly inhibited tumor growth, prevented invasion of mv4-11 cells, and improved overall survival [3]. | [in vivo]
Padnarsertib demonstrates a decrement of xenograft growth comparable with that of Sunitinib (HY-10255A). There are minimal Padnarsertib effects on the normal human RPTECs and no apparent toxicity in vivo[2].
Padnarsertib is currently being investigated in a phase I human clinical trial of patients with advanced solid malignancies and NHL[2].
Padnarsertib (oral administation; 100mg/kg or 200 mg/kg; twice a day; 14 days) demonstrates a decrement of xenograft growth without no significant weight loss. 8 hours after, Padnarsertib are measured at the end of the experiment in mouse plasma and tumors with 10757 ng/mL and 10647 ng/mL, respectively[3]. | Animal Model: | Mice[1] | | Dosage: | 100mg/kg or 200 mg/kg | | Administration: | Oral administation; 100mg/kg or 200 mg/kg; twice a day; 14 days | | Result: | Showed a significant decrease of xenograft growth in KPT-9274 treated mouse. |
| [IC 50]
PAK4: 100 nM (IC50); Nampt: 120 nM (IC50) | [References]
[1]. senapedis w, george r, mccauley d, et al. preclinical evaluation of novel pak4 allosteric modulators against triple negative breast cancer.
[2]. aboud oa, senapedis w, landesman y, et al. inhibition of pak4 attenuates renal cell carcinoma (rcc) growth.
[3]. mitchell s, orwick s, cannon m, et al. in vitro and in vivo anti-leukemic effects of kpt-9274, a reported pak4 allosteric modulator, in acute myeloid leukemia: promising results justifying further development in this disease. 57th annual meeting & exposition. orlando, fl december 5-8, 2015. |
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