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  • KPT-9274
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KPT-9274

Orally acitve allosteric inhibitor of PAK4

原价
¥2837-22437
价格
2270-17950
KPT-9274的二维码

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  • 货号: ajci13472
  • CAS: 1643913-93-2
  • 别名:
  • 分子式: C35H29F3N4O3
  • 分子量: 610.62
  • 纯度: >98%
  • 溶解度: ≥ 22.45mg/mL in DMSO
  • 储存: Store at -20°C
  • 库存: 现货

Background

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].

参考文献:
[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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