Amuvatinib

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型 RTK 抑制剂，可有效抑制 c-Kit、PDGFRα 和 Flt3，IC50 分别为 10 nM、40 nM 和 81 nM。

A novel RTK inhibitor that effectively inhibits c-Kit, PDGFRα and Flt3 with IC50 of 10 nM, 40 nM and 81 nM, respectively; also inhibits several mutants of c-Kit and Axl; inhibits prostate cancer cell proliferation (IC50=4-8 uM), promotes cell cycle arrest and apoptosis; completely inhibites phosphorylation of the HER members (HER1, 2, 3), binding of PI3K regulatory unit p85 to HER3 and downstream Akt activity in combination with Erlotinib; exhibits synergistic effect in LNCaP mouse xenograft model.Lung Cancer Phase 2 Discontinued(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.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.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. (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).

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. 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. 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. Cell Viability Assay Cell Line:Prostate cancer cell lines (LNCaP, PC-3 and DU-145)Concentration:0.1-10 μM Incubation Time:4 days Result:The IC50 for LNCaP and PC-3 was ~4 μM and 8 μM, respectively. Had only a modest effect on the viability of DU-145 cells. Western Blot Analysis Cell Line:LNCaP cells Concentration:2,5,10 μM Incubation Time:30 hoursResult:Akt activity (as measured by phosphorylation on Ser473) was significantly reduced at 10 μM.

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). Animal Model:Forty eight 6-7 week-old SCID male mice with LNCaP xenograft model 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%).

MP-470 | MP 470 | MP470 | HPK-56 | HPK56

Angiogenesis

c-Kit

c-Kit(D816H)|FLT3(D835Y)|PDGFRα(V561D)

Cancer

Lung Cancer

850879-09-3

447.5096

C23H21N5O3S

>98% (HPLC)

10 mM in DMSO

S=C(N1CCN(C2=C(OC3=CC=CC=C34)C4=NC=N2)CC1)NCC5=CC=C(OCO6)C6=C5

1-Piperazinecarbothioamide, N-(1,3-benzodioxol-5-ylmethyl)-4-benzofuro[3,2-d]pyrimidin-4-yl-

(-20℃)

With Ice Pack

≥ 2 years