ChemicalBook CAS DataBase List 1055986-67-8

1055986-67-8

Name	HPK 56 hydrochloride)
CAS	1055986-67-8
Molecular Formula	C23H22ClN5O3S
MDL Number	MFCD31813772
Molecular Weight	483.97
MOL File	1055986-67-8.mol

Chemical Properties

storage temp.	Store at -20°C
solubility	Soluble in DMSO

Hazard Information

Uses

Amuvatinib hydrochloride (MP470 hydrochloride) is an orally bioavailable multi-targeted tyrosine kinase inhibitor with potent activity against mutant c-Kit, PDGFRα, Flt3, c-Met and c-Ret. Amuvatinib hydrochloride (MP470 hydrochloride) is also a DNA repair suppressor through suppression of DNA repair protein RAD51, thereby disrupting DNA damage repair[1][2][3]. Antineoplastic activity[4].

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].

Animal Model:	Forty eight 6-7 week-old SCID male mice with LNCaP xenograft model^[2]
Dosage:	10 mg/kg and 20 mg/kg, 50 mg/kg
Administration:	Administered i.p. daily from days 1 to 24
Result:	Individual therapy showed modest tumor growth inhibition (TGI), while combination had a marked effect on TGI (45-65%).

IC 50

PDGFRα^V561D: 40 nM (IC₅₀); PDGFRα^D842V: 81 nM (IC₅₀); c-Kit^D816H: 10 nM (IC₅₀); c-Kit^V560G: 34 nM (IC₅₀); c-Kit^V654A: 127 nM (IC₅₀); c-Kit^D816V: 950 nM (IC₅₀)

storage

Store at -20°C

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. DOI:10.1007/s00280-012-1821-2
[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. DOI:10.1007/s00280-010-1380-3
[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. DOI:10.1007/s00280-012-2019-3
[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. DOI:10.1186/1471-2407-9-142

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