RKI-1447 is a type I kinase inhibitor that binds ATP binding sites through interactions with hinge regions and DFG motifs. RKI-1447 inhibits phosphorylation of ROCK substrates mLC-2 and MYPT-1 in human cancer cells, but has no effect on phosphorylation levels of AKT, MEK, and S6 kinases at concentrations up to 10 μM. RKI-1447 is also highly selective in inhibiting Rock-mediated cytoskeletal recombination. RKI-1447 inhibits breast cancer cell migration, invasion and anchor-independent tumor growth [1].
体内研究
In transgenic mouse models, RKI-1447 was highly effective in inhibiting breast tumor growth. The inhibitory effect of RKI-1447 on breast tumor growth was 87%, and the breast tumors of mice treated with RKI-1447 were 7.7 times smaller on average than those treated with carrier control [1].
体外研究
RKI-1447 is a type I kinase inhibitor that binds ATP binding sites through interactions with hinge regions and DFG motifs. RKI-1447 inhibits phosphorylation of ROCK substrates mLC-2 and MYPT-1 in human cancer cells, but has no effect on phosphorylation levels of AKT, MEK, and S6 kinases at concentrations up to 10 μM. RKI-1447 is also highly selective in inhibiting Rock-mediated cytoskeletal recombination. RKI-1447 inhibits breast cancer cell migration, invasion and anchor-independent tumor growth [1].
RKI-1447 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Med8a
1 µM
24 hours
Inhibited phosphorylation of MLC2, reduced cell proliferation
Cancers (Basel). 2019 Dec 26;12(1):73.
UW228-3
1.84 µM
72 hours
Inhibited tumorigenic capacity
Cancers (Basel). 2019 Dec 26;12(1):73.
D458
3 µM
24 hours
Inhibited phosphorylation of MLC2, reduced cell proliferation
Cancers (Basel). 2019 Dec 26;12(1):73.
D425
1 µM
24 hours
Inhibited phosphorylation of MLC2, reduced cell proliferation
Cancers (Basel). 2019 Dec 26;12(1):73.
DAOY
10 µM
24 hours
Inhibited phosphorylation of MLC2, reduced cell proliferation
Cancers (Basel). 2019 Dec 26;12(1):73.
NIH3T3 cells
1 µM
1 hour
Inhibited LPA-induced actin stress fiber formation but not PDGF-induced lamellipodia or bradykinin-induced filopodia formation
Cancer Res. 2012 Oct 1;72(19):5025-34.
H1299 human lung cancer cells
100 nM to 10 µM
1 hour
Inhibited phosphorylation levels of ROCK substrate MYPT-1
Cancer Res. 2012 Oct 1;72(19):5025-34.
MDA-MB-468 human breast cancer cells
100 nM to 10 µM
1 hour
Inhibited phosphorylation levels of ROCK substrates MLC-2 and MYPT-1
Cancer Res. 2012 Oct 1;72(19):5025-34.
MDA-MB-231 human breast cancer cells
100 nM to 10 µM
1 hour
Inhibited phosphorylation levels of ROCK substrates MLC-2 and MYPT-1
Cancer Res. 2012 Oct 1;72(19):5025-34.
MSC-4H-FC cells
0.5 µM
24 hours
Inhibition of RHO/ROCK signaling, completely abolishing 3D spheroid invasion of MSC-4H-FC cells
Neoplasia. 2018 Jan;20(1):44-56.
OCI-AML2 SRSF2 Mut cells
0.5 µM
24 hours
RKI-1447 caused G2/M cell-cycle arrest and abnormal spindle formation.
iScience. 2024 Mar 6;27(4):109443.
MOLM14 SRSF2 Mut cells
0.5 µM
24 hours
RKI-1447 induced mitotic catastrophe, cytoskeleton reorganization, and severe nuclear deformation, preventing cells from completing mitosis.
iScience. 2024 Mar 6;27(4):109443.
IPSC-derived HSPCs SRSF2 P95L
3 µM
48 hours
RKI-1447 showed higher toxicity to SRSF2 mutant cells.
iScience. 2024 Mar 6;27(4):109443.
Panc-1 cells
62.76 µM
72 hours
Evaluate the synergistic effect of RKI-1447 with HDAC inhibitors, showing slight synergism in Panc-1 cells
Pharmaceuticals (Basel). 2023 Feb 14;16(2):294.
MIA PaCa-2 cells
64.18 µM
72 hours
Evaluate the synergistic effect of RKI-1447 with HDAC inhibitors, showing synergism in MIA PaCa-2 cells
Pharmaceuticals (Basel). 2023 Feb 14;16(2):294.
786-O
2 µM
daily treatment
RKI 1447 selectively reduces colony forming ability and colony size in VHL-deficient CC-RCC
Oncogene. 2017 Feb 23;36(8):1080-1089.
RCC10
2 µM
daily treatment
RKI 1447 selectively reduces colony forming ability and colony size in VHL-deficient CC-RCC
Oncogene. 2017 Feb 23;36(8):1080-1089.
RCC4
2 µM
daily treatment
RKI 1447 selectively reduces colony forming ability and colony size in VHL-deficient CC-RCC
Oncogene. 2017 Feb 23;36(8):1080-1089.
RKI-1447 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
786-OT1 CC-RCC subcutaneous tumor model
Intraperitoneal injection
10 mg/kg
Daily for 18 days
Y-27632 inhibits growth of 786-OT1 CC-RCC tumors
Oncogene. 2017 Feb 23;36(8):1080-1089.
MMTV/neu transgenic mice
ErbB2 mammary tumor model
Intraperitoneal injection
200 mg/kg
Once daily for 14 days
Inhibited mammary tumor growth, with 60% of tumors being sensitive to RKI-1447, including 35% showing regression and 25% showing growth inhibition
Cancer Res. 2012 Oct 1;72(19):5025-34.
NSG mice
Primary human SRSF2-mutated AML xenograft model
Intraperitoneal injection
50 mg/kg
Daily for 21 days
RKI-1447 significantly reduced engraftment of SRSF2-mutated AML cells and prolonged mouse survival.
iScience. 2024 Mar 6;27(4):109443.
Mice
Adult mice
Intramuscular injection
80 µl, 10 µM
Twice, on the 1st and 3rd day, for 5 days
To study the inhibitory effect of RKI-1447 on Lrp4 synaptic expression, it was found that Lrp4 synaptic expression was reduced after RKI-1447 injection.
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