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Amuvatinib

MCE China：Amuvatinib

Brand：MedChemExpress (MCE)

Cat. No.HY-10206

CAS：850879-09-3

Synonyms：MP470; HPK 56

Purity：99.47%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：Amuvatinib (MP470) is an orally bioavailable multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret. Amuvatinib (MP470) is also a DNA repair suppressor through suppression of DNA repair protein RAD51, thereby disrupting DNA damage repair. Antineoplastic activity.

In Vitro：Amuvatinib (MP470) inhibits c-Kit (D816V), c-Kit (D816H), c-Kit (V560G), c-Kit (V654A), PDGFRα (D842V), and PDGFRα (V561D) with IC50s of 950 nM, 10 nM, 34 nM, 127 nM, 81 nM, and 40 nM, respectively[4]. Amuvatinib (MP470), a novel receptor tyrosine kinase (RTK) inhibitor has shown growth inhibitory activity against a variety of cancer cell lines. Amuvatinib (0.1-10 μM, 4 days incubation) is effective on LNCaP and PC-3 cells with IC50s of ~4 μM and 8 μM, respectively. When Erlotinib (10 μM) is combined with varying doses of Amuvatinib, the IC50 of Amuvatinib decreases to 2 μM on LNCaP cells[5]. Akt activity (as measured by phosphorylation on Ser473) is significantly reduced by 10 μM Amuvatinib (treated for 30 hours) alone but is not reduced by Erlotinib or Imatinib Mesylate (IM). Moreover, Amuvatinib plus Erlotinib completely abolished Akt phosphorylation in LNCaP cells with an unchanged total protein level of Akt[5].

In Vivo：Four LNCaP xenograft arms each with 12 mice are dosed intraperitoneally with DMSO (control) or Erlotinib 80 mg/kg or Amuvatinib (MP470) 50 mg/kg or Erlotinib 80 mg/kg plus Amuvatinib 50 mg/kg daily for 2 weeks and then observed for a further 11 days. Individual therapy with Amuvatinib or Erlotinib shows modest tumor growth inhibition (TGI), while Amuvatinib plus Erlotinib has a marked effect on TGI (45-65%). However, due to the high doses of Amuvatinib used, only five or one mouse remained alive in the combination arm at the end of treatment or at the end of the study, respectively. Therefore the Amuvatinib dose is reduced to 10 mg/kg or 20 mg/kg for the combination treatment. TGI in the group receiving 10 mg/kg Amuvatinib+80 mg/kg Erlotinib is not significantly different from the control group. However, mice receiving 20 mg/kg Amuvatinib+80 mg/kg Erlotinib have a significant TGI compared to the control group (p=0.01)[5].

IC50 & Target：PDGFRαV561D 40 nM (IC50) PDGFRαD842V 81 nM (IC50) c-KitD816H 10 nM (IC50) c-KitV560G 34 nM (IC50) c-KitV654A 127 nM (IC50) c-KitD816V 950 nM (IC50)

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References：

[1]. Choy G, et al. Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers. Cancer Chemother Pharmacol. 2012 Jul;70(1):183-90.  [Content Brief]

[2]. Tibes R, et al. A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Feb;71(2):463-71.  [Content Brief]

[3]. Baxter PA, et al. Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates. Cancer Chemother Pharmacol. 2011 Apr;67(4):809-12.  [Content Brief]

[4]. David J. Bearss, et al. Pharmaceutical formulations comprising salts of a protein kinase inhibitor and methods of using same. US20080226747A1.

[5]. Qi W, et al. MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer. BMC Cancer. 2009 May 11;9:142.  [Content Brief]