Rearranged during transfection (RET) is a receptor tyrosine kinase that acts as an oncogenic driver in multiple cancers. BLU-667 is a potent, selective, small-molecule RET inhibitor that demonstrates ≥10-fold increased potency over other multi-kinase inhibitors. It inhibited the kinase activity of wild-type RET with an IC50 of 0.4nM. BLU-667 also exhibited potent inhibitory activity against common oncogenic RET alterations, including RET V804L, RET V804M, RET M918T, and CCDC6-RET fusion, with IC50 values of 0.3, 0.4, 0.4, and 0.4nM, respectively. In Ba/F3 cells engineered to express a KIF5B-RET fusion, treatment with BLU-667 inhibited RET autophosphorylation with a cellular IC50 value of 5nM. BLU-667 also inhibited phosphorylation of RET, SHC, and ERK1/2 at concentrations of ≤10nM in RET-driven cell lines. In RET-driven murine models, BLU667 at doses as low as 10mg/kg (twice per day) exhibited concentration-dependent activity against KIF5B-RET Ba/F3 and KIF5B-RET V804L Ba/F3 allograft tumors. BLU-667 at doses of 3 to 60mg/kg also showed potent activity in a RET C634W MTC xenograft, and KIF5B-RET NSCLC and CCDC6-RET CRC patient-derived xenograft models[1].
Pralsetinib/普拉替尼 细胞实验
Cell Line
Concentration
Treated Time
Description
References
UM-SCC-47 cells
15 nM
48 hours
To evaluate the effect of Pralsetinib on the viability of UM-SCC-47 spheroids, results showed that Pralsetinib reduced cell viability and induced differentiation gene expression.
Cancer Res. 2022 Sep 2;82(17):3143-3157.
SCC4 cells
15 nM
48 hours
To evaluate the effect of Pralsetinib on the viability of SCC4 spheroids, results showed that Pralsetinib reduced cell viability and induced differentiation gene expression.
Cancer Res. 2022 Sep 2;82(17):3143-3157.
SCCIC1 cells
15 nM
48 hours
To evaluate the effect of Pralsetinib on the viability of SCCIC1 spheroids, results showed that Pralsetinib reduced cell viability and induced differentiation gene expression.
Cancer Res. 2022 Sep 2;82(17):3143-3157.
A431 cells
15 nM
48 hours
To evaluate the effect of Pralsetinib on the viability of A431 spheroids, results showed that Pralsetinib reduced cell viability and induced differentiation gene expression.
Cancer Res. 2022 Sep 2;82(17):3143-3157.
MCF7 cells
500 nmol/L
48 hours
To evaluate the inhibitory effect of Pralsetinib on ESR1 fusion-driven cell growth, results showed that Pralsetinib significantly inhibited the growth of MCF7 cells.
Cancer Res. 2023 Oct 2;83(19):3237-3251.
T47D cells
500 nmol/L
48 hours
To evaluate the inhibitory effect of Pralsetinib on ESR1 fusion-driven cell growth, results showed that Pralsetinib significantly inhibited the growth of T47D cells.
Cancer Res. 2023 Oct 2;83(19):3237-3251.
Pralsetinib/普拉替尼 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SHO mice
TPC1-derived TSR tumor model
Oral gavage
30 mg/kg
Once daily for 7 days
Evaluate the inhibitory effect of BLU667 combined with Aurora or MEK1/2 kinase inhibitors on TSR tumors, showing that combination therapy significantly reduces tumor volume.
Drug Resist Updat. 2023 May;68:100958.
NCG mice
A431 subcutaneous xenograft model
Peritumoral injection
48 mg/kg
Once daily for 12 days
To evaluate the inhibitory effect of Pralsetinib on the growth of A431 xenografts, results showed that Pralsetinib significantly inhibited tumor growth and induced differentiation.
Cancer Res. 2022 Sep 2;82(17):3143-3157.
SCID/beige mice
WHIM18 PDX model
Oral
30 mg/kg bw per day
Daily administration until study endpoint
To evaluate the inhibitory effect of Pralsetinib on ESR1 fusion-driven tumor growth, results showed that Pralsetinib significantly inhibited the growth of WHIM18 PDX tumors.
RET-altered Non Small Cell Lun... 展开 >>g Cancer
Medullary Thyroid Cancer
RET-altered Papillary Thyroid Cancer
RET-altered Colon Cancer
RET-altered Solid Tumors 收起 <<
RET-altered Non Small Cell Lun... 展开 >>g Cancer
Medullary Thyroid Cancer
RET-altered Papillary Thyroid Cancer
RET-altered Colon Cancer
RET-altered Solid Tumors 收起 <<
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