AMG-510 is a specific covalent inhibitor of K-RAS(G12C) ,which irreversibly inhibits KRAS G12C by locking it in an inactive GDP-bound state. AMG-510 selectively targets the KRAS p.G12C mutant and shows potential antineoplastic activity. KRAS encodes a key signalling protein in tumours, and the G12C KRAS mutation is relatively common in some cancer types. Treatment of KRAS p.G12C lines with covalent KRASG12C inhibitor AMG 510 can increase the expression of HLA[1].AMG 510 is the first drug candidate to target this mutation[1]. In clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients[1].
作用機(jī)制
AMG-510 selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form. KRASG12C can be targeted with covalent small molecule inhibitor AMG-510 which react with the mutant cysteine adjacent to the switch II pocket (SIIP), locking KRAS in its inactive GDP-bound state[1].
Sotorasib/索托拉西布 細(xì)胞實(shí)驗(yàn)
Cell Line
Concentration
Treated Time
Description
References
MIAPACA2 cells
40 nM
72 h
Investigate the effect of Sotorasib on MIAPACA2 cells, results showed that ALDH1A1 knockout enhanced the effect of Sotorasib
Redox Biol. 2024 Nov;77:103361.
H2122 cells
100 nM
72 h
Investigate the effect of Sotorasib on H2122 cells, results showed that ALDH1A1 knockout enhanced the effect of Sotorasib
Redox Biol. 2024 Nov;77:103361.
MIA-PaCa-2 cells
30 nM
2 days
Suppressed the activation of MEK/ERK, leading to cell growth inhibition and increased protein aggregation
Science. 2023 Sep 8;381(6662):eabn4180.
H358 cells
30 nM
2 days
Suppressed the activation of MEK/ERK, leading to cell growth inhibition and increased protein aggregation
Science. 2023 Sep 8;381(6662):eabn4180.
MiaPaCa2
6 nM
72 h
To evaluate the synergistic effects of Sotorasib with various drugs and identify potential combination therapies
Mol Oncol. 2025 Feb;19(2):295-310.
H358
1 μM
72 h
Evaluate the anti-proliferative effect of Sotorasib on KRASG12C mutant lung cancer cells
Nat Commun. 2024 Aug 30;15(1):7554.
H23
1 μM
72 h
Evaluate the anti-proliferative effect of Sotorasib on KRASG12C mutant lung cancer cells
Nat Commun. 2024 Aug 30;15(1):7554.
H1792
1 μM
72 h
Evaluate the anti-proliferative effect of Sotorasib on KRASG12C mutant lung cancer cells
Nat Commun. 2024 Aug 30;15(1):7554.
H2030
1 μM
72 h
Evaluate the anti-proliferative effect of Sotorasib on KRASG12C mutant lung cancer cells
Nat Commun. 2024 Aug 30;15(1):7554.
H2122
1 μM
72 h
Evaluate the anti-proliferative effect of Sotorasib on KRASG12C mutant lung cancer cells
Nat Commun. 2024 Aug 30;15(1):7554.
MIA PaCa-2
5 μM
> 2 weeks
Establish sotorasib-resistant cells
J Biomed Sci. 2023 Jun 29;30(1):50.
NCI-H23
5 μM
> 2 weeks
Establish sotorasib-resistant cells
J Biomed Sci. 2023 Jun 29;30(1):50.
LU65
5 μM
> 2 weeks
Establish sotorasib-resistant cells
J Biomed Sci. 2023 Jun 29;30(1):50.
Sotorasib/索托拉西布 動(dòng)物實(shí)驗(yàn)
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
UMUC3 and H358 subcutaneous xenograft models
Oral gavage
100 mg/kg
Once daily until the end of the experiment
To evaluate the antitumor efficacy of Sotorasib and its combination with radiolabeled P1B7 IgG. Results showed that the combination of Sotorasib with radiolabeled P1B7 IgG significantly inhibited tumor growth.
Cancer Res. 2025 Jan 15;85(2):329-341
Nude mice
MIAPACA2 xenograft model
Oral
30 mg/kg
Once daily for 2 weeks
Investigate the anti-tumor effect of Sotorasib in MIAPACA2 xenograft model, results showed that Sotorasib significantly inhibited tumor growth
Redox Biol. 2024 Nov;77:103361.
ICR-SCID mice
PDAC (MIA PaCa-2) cell-derived xenograft model
Oral
25 mg/kg
Daily for 3 weeks
The combination of KPT9274 and Sotorasib significantly reduced tumor volumes, tumor weights, and tumor sizes.
Mol Cancer Ther. 2023 Dec 1;22(12):1422-1433.
ICR-SCID mice
MIA PaCa-2 cell-derived tumor xenograft model
Oral
25 mg/kg
Daily administration for 3 weeks
Significant reduction in tumor volumes, tumor weights, and tumor sizes
Mol Cancer Ther. 2023 Dec 1;22(12):1422-1433.
Mice
MIA-PaCa-2 xenograft tumor model
Oral
30 mg/kg
Daily for 6 weeks
Initially sensitive to sotorasib but relapsed after 6 weeks, with increased protein aggregation and restored proteostasis in relapsed tumors
Science. 2023 Sep 8;381(6662):eabn4180.
Mice
Subcutaneous tumor model
Oral
30 mg/kg
Once daily for 3 weeks
Evaluate the in vivo anti-tumor effect of Sotorasib on KRASG12C mutant tumors
Nat Commun. 2024 Aug 30;15(1):7554.
NOD/SCID mice
Subcutaneous xenograft model
Oral
10 mg/kg
Once daily for 14 days
Evaluate the effect of combined treatment with sotorasib and BRAF inhibitor
J Biomed Sci. 2023 Jun 29;30(1):50.
Mice
NCI-H358-R xenograft model
Subcutaneous injection
250 mg/kg
4 days on, 2 days off
Evaluate the efficacy of GNE-7883 in combination with sotorasib in overcoming KRAS G12C inhibitor resistance
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