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Amuvatinib hydrochloride

Catalog No. T14282 CAS 1055986-67-8

Synonyms: HPK 56 hydrochloride, MP470 hydrochloride

Amuvatinib hydrochloride (MP470 hydrochloride) is an orally administred multi-targeted tyrosine kinase inhibitor that exhibits strong efficacy against mutant forms of c-Kit, PDGFRα, Flt3, c-Met, and c-Ret, while also acting as a suppressor of DNA repair by inhibiting the RAD51 protein, which is crucial for repairing DNA damage[1][2][3]. This dual mechanism contributes to its antineoplastic activity[4].

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Amuvatinib hydrochloride Chemical Structure

Amuvatinib hydrochloride, CAS 1055986-67-8

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Description	Amuvatinib hydrochloride (MP470 hydrochloride) is an orally administred multi-targeted tyrosine kinase inhibitor that exhibits strong efficacy against mutant forms of c-Kit, PDGFRα, Flt3, c-Met, and c-Ret, while also acting as a suppressor of DNA repair by inhibiting the RAD51 protein, which is crucial for repairing DNA damage[1][2][3]. This dual mechanism contributes to its antineoplastic activity[4].
Targets&IC50	PDGFRα (D842V):81 nM, c-Kit (D816H):10 nM, c-Kit (V560G):34 nM, c-Kit (D816V):950 nM, PDGFRα (V561D):40 nM, c-Kit (V654A):127 nM
In vitro	Amuvatinib (MP470), a novel receptor tyrosine kinase (RTK) inhibitor has shown growth inhibitory activity against a variety of cancer cell lines. 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 (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. However it is not reduced by Erlotinib or Imatinib Mesylate (IM). 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. 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]. Individual therapy with Amuvatinib or Erlotinib shows modest tumor growth inhibition (TGI), while Amuvatinib plus Erlotinib has a marked effect on TGI (45-65%). But, 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.

Synonyms	HPK 56 hydrochloride, MP470 hydrochloride
Molecular Weight	483.97
Formula	C23H22ClN5O3S
CAS No.	1055986-67-8

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

References and Literature

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

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Keywords

Amuvatinib hydrochloride 1055986-67-8 Others HPK 56 hydrochloride MP470 hydrochloride MP-470 Hydrochloride HPK56 Hydrochloride MP 470 Hydrochloride HPK 56 Hydrochloride Amuvatinib Hydrochloride MP470 Hydrochloride HPK-56 Hydrochloride inhibitor inhibit

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