c-KIT is a tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. c-KIT is a proto-oncogene. Activating or gain of function mutations in c-KIT have been identified in a variety of tumors[3].
Amuvatinib, also termed MP470, is an inhibitor of various mutant c-KIT kinases. The inhibitory IC50s of MP470 against c-KIT(D816V), c-KIT(D816H), c-KIT(V560G), c-KIT(V654A) were 0.95 μM, 0.01 μM, 0.034 μM and 0.127 μM, respectively. The IC50 for MP470 on OVCAR-3 cells proliferation was 0.9 μM[3]. According to another report, the IC50 for MP470 on prostate cancer LNCaP and PC-3 cells were ~4 μM and 8 μM, respectively, when incubated for 4 days. Flow cytometric analysis revealed that 48h treatment of MP470 to LNCaP cells at the concentration of 10 μM induced 28% of apoptosis[4].
In a HT-29 xenograft model, MP470 was i.p. administrated at the doses of 10 or 20 mg/kg at the schedule of 5 times a week for 2 weeks. Both doses significantly inhibited tumor growth. In an A549 xenograft model, MP470 was orally administrated at the doses of 50, 100, or 200 mg/kg, also 5 times a week for 2 weeks. All three doses exhibited anti-tumor activity[3]. In another LNCaP xenograft model, MP470 was i.p. dosed at 50 mg/kg daily for 24 days. This dose in combination with Erlotinib had a marked effect with tumor growth inhibition of 45-65%, while both drugs were of modest activity as a single agent[4].
Amuvatinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U266 cells
25 µM
24, 48, and 72 hours
Cell death rates of 28%, 40%, and 55%
J Hematol Oncol. 2013 Dec 10;6:92.
RAW 264.7 cells
250 ng
24 hours
To evaluate the effect of BMP7 on MAPK14 and SMAD1/5/9 phosphorylation, results showed that BMP7 treatment reduced MAPK14 expression and increased SMAD1/5/9 phosphorylation.
Nat Commun. 2020 Sep 24;11(1):4840.
Maturing neurons
10 µM
24 hours
Amuvatinib is neuroinhibitory to maturing neurons with an EC50=2.5 μM
FEBS J. 2023 Oct;290(20):4950-4965.
344SQR cells
0, 1, 10, 100 µM
24, 48, 72 hours
To evaluate the effect of SHP099 on the proliferation of 344SQR cells, results showed that SHP099 did not significantly inhibit cell proliferation.
Cancer Immunol Res. 2020 Jul;8(7):883-894.
U87MG cells
10 µM
48 and 72 hours
To evaluate the effect of Amuvatinib on the viability of U87MG cells, results showed that Amuvatinib single treatment significantly reduced cell viability, and the combination with LPS further decreased cell viability.
Sci Rep. 2021 Jan 14;11(1):1333.
344-SQ NSCLC cells
5 nM and 15 nM
48 hours
To evaluate the antitumor effect of IACS-010759 in combination with radiotherapy, results showed that in the PD-1 resistant model, IACS-010759 combined with radiotherapy significantly inhibited clonogenic formation
J Immunother Cancer. 2020 Jun;8(1):e000289.
CD4+ T cells
250 ng
60 minutes
To evaluate the effect of BMP7 on MAPK14 and SMAD1/5/9 phosphorylation, results showed that BMP7 treatment reduced MAPK14 expression and increased SMAD1/5/9 phosphorylation.
Nat Commun. 2020 Sep 24;11(1):4840.
U266 cells
5, 10, or 25 µM
Inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation
J Hematol Oncol. 2013 Dec 10;6:92.
Amuvatinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
344SQR tumor model
Intraperitoneal injections
10 mg/kg
Twice per week for two weeks
To evaluate the effect of BMP7 inhibition on tumor growth and survival, results showed that BMP7 inhibition significantly reduced tumor growth and extended survival.
Nat Commun. 2020 Sep 24;11(1):4840.
Mice
Anti-PD1 resistant lung cancer model
Intraperitoneal injection
200 µg
Days 5, 8, 11, 14, 21, 28, 35, and 42
This nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice.
J Nanobiotechnology. 2022 Sep 19;20(1):417
Mice
Anti-PD1-resistant metastatic lung cancer model
Intraperitoneal injection
200 mg aPD1, 50 mg aCTLA4 or NF-aCTLA4
Administered on days 7, 11, and 14, with aPD1 treatment continued on days 21, 28, 35, and 42
To evaluate the efficacy of NBTXR3 combined with anti-PD1 and nonfucosylated anti-CTLA4 in immunoradiotherapy, the results showed that this combination significantly upregulated the activities of a wide range of antitumor immune pathways, reduced the abundance of regulatory suppressor T cells, and significantly increased animal survival to 75%.
Front Immunol. 2022 Nov 3;13:1022011
129 Sv/Ev mice
Bilateral lung adenocarcinoma model
Subcutaneous injection
3 mg/kg
Every 4 days for 7 cycles
To evaluate the antitumor efficacy of RDB 1462 in combination with radiotherapy, results showed that RDB 1462 significantly reduced tumor volume and prolonged survival.
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