AKT is the central node of PI3K/AKT/mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound[1]. AK316078 is an ATP-competitive pan AKT inhibitor with IC50 values of 13, 66, 57 nM for AKT 1, 2 and 3 (measured by enzyme assays), respectively[2]. AZD5363 on concentration of 0.3 – 10 μM effectively inhibited phosphorylation of S6 and 4E-BP1, which are the downstream of AKT, in LNCaP and BT474 cells, whereas it increased phosphorylation of AKT at both Ser473 and Thr308 like other ATP-competitive AKT inhibitors. Treatment with 3 μM AZD5363 for 2h can induce FOXO3a nuclear translocation. In cell growth inhibition assays, HER2+ and ER+ breast cancer cell lines showed most consistently sensitivity to AZD5363 (<3 μM). Oral administration of AZD5363 at 100 mg/kg twice daily resulted in 80% inhibition in HER2+ amplified, PIK3CA mutant BT474c xenografts. AZD5363 at 150 mg/kg twice daily caused pronounced tumor regression (129% inhibition), whereas 75 mg/kg twice daily resulted in 111% inhibition in HER2+ amplified, PIK3CA mutant HCC-1954 breast cancer xenograft[3]. Several clinical trials of AZD5363, including a completed phase 2 study of treatment for invasive breast cancer, have been done (see in https://clinicaltrials.gov/).
作用机制
AZD5363 is an ATP-competitive AKT inhibitor.
Capivasertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
T47D
0.01 –10μM
72 h
To evaluate the inhibitory effect of Capivasertib on T47D cells, results showed that T47D cells had an IC50 value of 2.1 μM and were more sensitive to Capivasertib than MCF-7 cells.
Br J Cancer. 2024 Nov;131(9):1543-1554.
MCF-7
0.01 –10μM
72 h
To evaluate the inhibitory effect of Capivasertib on MCF-7 cells, results showed that MCF-7 cells had an IC50 value of 7.5 μM and were less sensitive to Capivasertib than T47D cells.
Br J Cancer. 2024 Nov;131(9):1543-1554.
Onc-negativeRAS/PI3K murine cell lines
10 μM
2 days
To evaluate the effect of Capivasertib on cell proliferation and apoptosis. Results showed that Capivasertib significantly inhibited cell proliferation and induced apoptosis.
Cancer Res. 2022 Apr 15;82(8):1589-1602.
MCF-7
500 nM
6 days
To evaluate the growth inhibitory effect of Capivasertib in MCF-7 cells, the results showed that the triple combination (fulvestrant, CDK4/6i, and AKTi) significantly inhibited the growth of fulvestrant-resistant cells
Nat Commun. 2021 Aug 25;12(1):5112.
T47D
200 nM
6 days
To evaluate the growth inhibitory effect of Capivasertib in T47D cells, the results showed that the triple combination (fulvestrant, CDK4/6i, and AKTi) significantly inhibited the growth of fulvestrant-resistant cells
Nat Commun. 2021 Aug 25;12(1):5112.
ZR-75-1
150 nM
6 days
To evaluate the growth inhibitory effect of Capivasertib in ZR-75-1 cells, the results showed that the triple combination (fulvestrant, CDK4/6i, and AKTi) significantly inhibited the growth of fulvestrant-resistant cells
Nat Commun. 2021 Aug 25;12(1):5112.
AN3-CA
1 µM
74 h
To validate the combination activity of Capivasertib with AZD5991 in endometrial cancer cells, results showed induction of apoptosis in AN3-CA and MFE-296 cells.
Cancer Discov. 2024 May 1;14(5):846-865.
MFE-296
1 µM
74 h
To validate the combination activity of Capivasertib with AZD5991 in endometrial cancer cells, results showed induction of apoptosis in AN3-CA and MFE-296 cells.
Cancer Discov. 2024 May 1;14(5):846-865.
HCC70
500 nM
4 days
To evaluate the sensitivity of HCC70 cells to Capivasertib, the results showed that Capivasertib significantly inhibited cell proliferation.
Oncogene. 2022 Nov;41(46):5046-5060.
EVSA-T
1 µM
4 days
To evaluate the sensitivity of EVSA-T cells to Capivasertib, the results showed that Capivasertib significantly inhibited cell proliferation.
Oncogene. 2022 Nov;41(46):5046-5060.
SNU-1196-GR
2 μM
72 h
To evaluate the sensitivity of SNU-1196-GR cells to Capivasertib, results showed that Capivasertib reduced the IC50 value of GEM.
Int J Biol Sci. 2023 May 21;19(9):2772-2786.
SSP-25-GR
2 μM
24 h
To evaluate the effect of Capivasertib on hENT1 expression in SSP-25-GR cells, results showed that Capivasertib enhanced hENT1 expression.
Int J Biol Sci. 2023 May 21;19(9):2772-2786.
MDA-MB-231 cells
0.1 μM
48 h
To investigate the effect of Capivasertib on DOX-induced cell death in DNAJC12-overexpressing cells, results showed that Capivasertib significantly decreased cell viability in the DNAJC12-overexpressing group, approaching the level observed with DOX treatment alone in the negative control group.
Redox Biol. 2024 Apr;70:103035.
MCF-7 cells
0.1 μM
48 h
To investigate the effect of Capivasertib on DOX-induced cell death in DNAJC12-knockdown cells, results showed that Capivasertib significantly decreased cell viability in the negative control group, approaching the level observed with DOX treatment alone in the DNAJC12 knockdown group.
Redox Biol. 2024 Apr;70:103035.
Capivasertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
SCID mice
MCF7 xenograft model
Oral
150 mg/kg
Twice daily for 28 days
AZD5363 treatment significantly reduced (22%) mean tumor volume (MTV) of MCF7 parental tumors whereas it had no effect on MCF7 CR2.5 tumors, at day 18 of treatment.
Oncotarget. 2018 Apr 20;9(30):21444-21458.
Mice
TC mice
Oral
100 mg/kg
Daily for eight days, stopped for two days for recovery, and continued for two more days
To evaluate the effect of Capivasertib alone or in combination with RMC-4550 on tumor burden. Results showed that Capivasertib alone was ineffective in vivo, but the combination with RMC-4550 significantly reduced tumor burden.
Cancer Res. 2022 Apr 15;82(8):1589-1602.
Mice
Breast cancer xenograft model
Oral
100 mg/kg
5 days per week for 7 weeks
To evaluate the anti-tumor effect of Capivasertib in a breast cancer xenograft model, the results showed that the triple combination (fulvestrant, CDK4/6i, and AKTi) significantly inhibited tumor growth and prevented tumor recurrence
Nat Commun. 2021 Aug 25;12(1):5112.
Mice
PTEN-deficient prostate cancer PDX model
Intraperitoneal injection
2.5 mg/kg
Daily, continuous treatment
To evaluate whether the CX3CR1 inhibitor JMS-17-2 could sensitize PTEN-deficient prostate cancer to the AKT inhibitor Capivasertib. The results showed that JMS-17-2 significantly enhanced the inhibitory effect of Capivasertib on PDX growth.
J Clin Invest. 2024 May 23;134(14):e175949
Mice
NOMO-1 xenograft model
Oral
10 mg/kg
Twice daily for 28 days
To evaluate the in vivo activity of Capivasertib with AZD5991 in the NOMO-1 xenograft model, results showed significant tumor growth inhibition.
Cancer Discov. 2024 May 1;14(5):846-865.
Female nude mice
HCC70 tumor xenograft model
Oral
130 mg/kg
Twice daily for 4 days
To evaluate the anti-tumor activity of Capivasertib in combination with AZD5991 in the HCC70 tumor xenograft model, the results showed that the combination significantly inhibited tumor growth.
Oncogene. 2022 Nov;41(46):5046-5060.
BALB/c nude mice
SNU-1196-GR xenograft model
Oral gavage
100 mg/kg
Five times per week for 3 weeks
To evaluate the effect of Capivasertib in combination with GEM on tumor growth in the SNU-1196-GR xenograft model, results showed that the combination treatment significantly inhibited tumor growth.
Int J Biol Sci. 2023 May 21;19(9):2772-2786.
BALB/c nude mice
MDA-MB-231 cell-derived xenograft model
Intraperitoneal injection
50 mg/kg
Every three days for a total of 5 injections
To investigate the reversal effect of Capivasertib on DNAJC12-induced DOX resistance, results showed that the combination of Capivasertib and DOX significantly reduced tumor volume in the DNAJC12-overexpressing group, reversing DOX resistance.
Redox Biol. 2024 Apr;70:103035.
Capivasertib 动物研究
Dose
Mice (p.o.): min = 50 mg/kg[4], max = 300 mg/kg[3]
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