Mouse Double Minute 2 (MDM2) is an oncogene that contributes to the progression and metastasis of breast cancer and is associated with poor prognosis in breast cancer patients. SP-141 is a specific MDM2 inhibitor that directly binds to the MDM2 protein with a Ki value of 28±6nM in the FP-based assay and a KD value of 43 nM in the Biacore assay. SP-141 inhibited breast cancer cell growth (MCF-7/p53 wild-type, MCF-7/p53 knockdown, MDA-MB-468/p53 mutant, MDA-MB-231/p53 mutant, and MDA-MB-435/p53 mutant) with IC50 values ranging from 0.39 – 0.91μM. In MCF-7/p53 wild-type, MCF-7/p53 knockdown, and MDA-MB-468/p53 mutant cells, SP-141 at a concentration of 1μM increased apoptosis rate 14-, 7-, and 11-fold, respectively, relative to control cells. SP-141 also significantly induced cell cycle arrest in the G2 phase at a concentration of 0.5μM. The expression of cleaved PARP and Bax was increased, while that of Bcl-2 and Cyclin E was decreased in SP-141-treated breast cancer cells in a p53-independent manner. Intraperitoneal injection of SP-141 at a dose of 40mg/kg/day for 42 and 30 days inhibited tumor growth in nude mice bearing MCF-7 (by ~82%) and MDA-MB-468 (by ~80%) xenograft tumors, respectively.[1]
作用机制
SP-141 is a specific MDM2 inhibitor that shows a strong binding capacity for the MDM2 protein. The binding site of SP-141 is in the hydrophobic groove of MDM2. SP-141 destabilizes the MDM2 protein in vitro by promoting its ubiquitination.[1]
SP-141 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MDA-MB-231 cells
5 µg/mL
120 minutes
To evaluate the cellular uptake ability of SP141FcNP, results showed that SP141FcNP exhibited the best cellular uptake in all cell lines, and the addition of free Fc fragments significantly reduced the uptake of SP141FcNP.
J Control Release. 2016 Sep 10;237:101-14
MCF7 cells
5 µg/mL
120 minutes
To evaluate the cellular uptake ability of SP141FcNP, results showed that SP141FcNP exhibited the best cellular uptake in all cell lines, and the addition of free Fc fragments significantly reduced the uptake of SP141FcNP.
J Control Release. 2016 Sep 10;237:101-14
Caco2 cells
5 µg/mL
120 minutes
To evaluate the transepithelial transport ability of SP141FcNP, results showed that SP141FcNP had better transepithelial permeability (Papp = 29.1 × 10−5 cm/s) than both free SP141 (Papp = 7.0 × 10−5 cm/s) and non-targeted SP141NP (Papp = 15.5 × 10−5 cm/s).
J Control Release. 2016 Sep 10;237:101-14
Hep3B cells
100 µM
15-120 minutes
To evaluate the effect of SP-141 on MDM2 expression in Hep3B cells. Results showed no significant effect on [18F]1 uptake.
Pharmaceuticals (Basel). 2021 Apr 13;14(4):358
HepG2 cells
1-10 µM
21 hour
To evaluate the effect of SP-141 on MDM2 expression in HepG2 cells. Results showed a significant decrease in [18F]1 uptake (~68 %/mg protein vs. 18.5 %/mg protein).
Pharmaceuticals (Basel). 2021 Apr 13;14(4):358
MCF-7 cells
1-10 µM
21 hour
To evaluate the effect of SP-141 on MDM2 expression in MCF-7 cells. Results showed a significant decrease in [18F]1 uptake (≤18.5 ± 0.0 %/mg protein vs. 71.4 ± 0.0 %/mg protein).
Pharmaceuticals (Basel). 2021 Apr 13;14(4):358
DAOY
0.25–1 µM
24 hours
To evaluate the effects of SP-141 on MDM2, p53, and p21cip1 levels. Results showed significant reduction in MDM2, increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis.
Cells. 2020 Jul 1;9(7):1592
U87MG
0.25–1 µM
24 hours
To evaluate the effects of SP-141 on MDM2, p53, and p21cip1 levels. Results showed significant reduction in MDM2, increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis.
Cells. 2020 Jul 1;9(7):1592
Mia-Paca-2 cells
0.41 µM (IC50)
72 hours
SP141 inhibited Mia-Paca-2 cell growth with IC50 values of 0.38-0.50 μM, inducing apoptosis and G2/M phase arrest
Gastroenterology. 2014 Oct;147(4):893-902. e2
AsPC-1 cells
0.36 µM (IC50)
72 hours
SP141 inhibited AsPC-1 cell growth with IC50 values of 0.38-0.50 μM, inducing apoptosis and G2/M phase arrest
Gastroenterology. 2014 Oct;147(4):893-902. e2
Panc-1 cells
0.50 µM (IC50)
72 hours
SP141 inhibited Panc-1 cell growth with IC50 values of 0.38-0.50 μM, inducing apoptosis and G2/M phase arrest
Gastroenterology. 2014 Oct;147(4):893-902. e2
HPAC cells
0.38 µM (IC50)
72 hours
SP141 inhibited HPAC cell growth with IC50 values of 0.38-0.50 μM, inducing apoptosis and G2/M phase arrest
Gastroenterology. 2014 Oct;147(4):893-902. e2
MCF-10A
0-25 µM
72 hours
Evaluate the effect of SP-141 on normal breast epithelial cell viability, IC50 value of 11.74 μM
Nat Commun. 2014 Oct 1;5:5086
MDA-MB-435/p53 mt
0-25 µM
72 hours
Evaluate the effect of SP-141 on breast cancer cell viability, IC50 values of 0.39–0.91 μM
Nat Commun. 2014 Oct 1;5:5086
MDA-MB-231/p53 mt
0-25 µM
72 hours
Evaluate the effect of SP-141 on breast cancer cell viability, IC50 values of 0.39–0.91 μM
Nat Commun. 2014 Oct 1;5:5086
MDA-MB-468/p53 mutant (mt)
0-25 µM
72 hours
Evaluate the effect of SP-141 on breast cancer cell viability, IC50 values of 0.39–0.91 μM
Nat Commun. 2014 Oct 1;5:5086
MCF-7/p53 knockdown (KD)
0-25 µM
72 hours
Evaluate the effect of SP-141 on breast cancer cell viability, IC50 values of 0.39–0.91 μM
Nat Commun. 2014 Oct 1;5:5086
MCF-7
0-25 µM
72 hours
Evaluate the effect of SP-141 on breast cancer cell viability, IC50 values of 0.39–0.91 μM
Nat Commun. 2014 Oct 1;5:5086
SP-141 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rice
Rice blast model
Spray
50 μM
Single treatment
Effective control of rice blast
Plant Commun. 2024 Feb 12;5(2):100724
Athymic mice
HepG2 tumor xenograft model
Intraperitoneal injection
1.2 mg/mouse
Single dose, 30 minutes before [18F]1 injection
To evaluate the effect of SP-141 on [18F]1 uptake in HepG2 tumor xenografts. Results showed no significant change in [18F]1 tumor uptake (3.2 ± 0.7 %ID/g vs. 3.0 ± 0.7 %ID/g).
Pharmaceuticals (Basel). 2021 Apr 13;14(4):358
Nude mice
Panc-1 and AsPC-1 xenograft and orthotopic models
Intraperitoneal injection
40 mg/kg/d
Once daily for 18 days (Panc-1 xenograft model) or 35 days (Panc-1 orthotopic model) or 25 days (AsPC-1 orthotopic model)
SP141 significantly inhibited Panc-1 xenograft tumor growth (75% reduction in tumor volume on Day 18) and led to almost complete regression of orthotopic tumors
Gastroenterology. 2014 Oct;147(4):893-902. e2
Nude mice
MCF-7 and MDA-MB-468 xenograft models
Intraperitoneal injection
40 mg/kg/day
5 days per week for 42 days (MCF-7 model) or 30 days (MDA-MB-468 model)
Evaluate the inhibitory effect of SP-141 on xenograft tumor growth, results showed SP-141 significantly inhibited tumor growth (~80%) with no apparent host toxicity
Nat Commun. 2014 Oct 1;5:5086
NCG mice
U87MG glioblastoma and DAOY medulloblastoma intracranial xenograft models
Intraperitoneal injection
40 mg/kg/day
5 days/week for 4 weeks
To evaluate the antitumor activity of SP-141 in vivo against glioblastoma and medulloblastoma. Results showed SP-141 significantly decreased tumor growth (4- to 9-fold) without discernible toxicity.
Cells. 2020 Jul 1;9(7):1592
Female athymic nude mice
MDA-MB-231 orthotopic tumor model
Oral gavage
80 or 160 mg/kg/day
5 days/week for 24 days
To evaluate the in vivo antitumor efficacy of SP141FcNP, results showed that SP141FcNP at doses of 80 and 160 mg/kg inhibited tumor growth by approximately 79% and 90%, respectively, with no apparent host toxicity observed.
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