KPT-9274
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].
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.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 610.62 |
| Cas No. | 1643913-93-2 |
| Formula | C35H29F3N4O3 |
| Solubility | ≥22.45 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH |
| Chemical Name | (1Z,2E)-3-(6-aminopyridin-2-yl)-N-((5-(4-(4,4-difluoropiperidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylimidic acid |
| SDF | Download SDF |
| Canonical SMILES | FC1=CC=C(C2=CC(C3=CC=C(C(N4CCC(F)(F)CC4)=O)C=C3)=CC5=C2OC(C/N=C(O)/C([H])=C([H])/C6=NC(N)=CC=C6)=C5)C=C1 |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
Quality Control & MSDS
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Chemical structure
