MRTX1133 is a noncovalent, potent, and selective inhibitor targeting KRAS G12D. It occupies the switch II pocket optimally and extends three substituents to facilitate favorable interactions with the protein, resulting in an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 blocks SOS1-catalyzed nucleotide exchange and/or the formation of the KRAS G12D/GTP/RAF1 complex, thereby impeding mutant KRAS-dependent signal transduction. It selectively inhibits KRAS G12D mutant tumor cells while sparing KRAS wild-type cells. MRTX1133 exhibits single-digit nanomolar activity in cellular assays and demonstrates significant efficacy in tumor models with KRAS G12D mutations[1][2].
体内研究
MRTX1133 demonstrates efficacy in a xenograft mouse tumor model harboring the KRAS G12D mutation[1].
体外研究
MRTX1133 inhibits ERK phosphorylation in the AGS cell line, with an IC50 ranging from 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, MRTX1133 exhibits an IC50 of 6 nM against AGS cells (KRAS G12D), while showing over 500-fold selectivity against MKN1, a cell line dependent on KRAS for growth and survival due to wild-type KRAS amplification[1].
MRTX1133 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PDAC-K cells (2138-K, 3213-K, 1245-K, PANC1-K)
2 µmol/L
8 hours
MRTX1133 treatment decreased pERK signaling and upregulates BIM expression in 3D collagen cultures.
Cancer Res. 2024 Nov 4;84(21):3629-3639.
PDAC cells (2138, 3213, 1245, PANC1)
0.5 µmol/L
72 hours
MRTX1133, even though it blocked ERK1/2 phosphorylation, failed to suppress the growth of these cell lines.
Cancer Res. 2024 Nov 4;84(21):3629-3639.
PDAC cells (2138, 3213, 1245, PANC1)
0.5 µmol/L
72 hours
MRTX1133 suppressed ERK1/2 phosphorylation and effectively blocked the growth of mouse and human PDAC cell lines.
Cancer Res. 2024 Nov 4;84(21):3629-3639.
ASPC1 cells
60 nmol/L
72 hours
MRTX1133 and afatinib combination showed synergistic effects
Cancer Res. 2023 Sep 15;83(18):3001-3012.
SUIT2 cells
60 nmol/L
72 hours
MRTX1133 treatment dramatically decreased pMEK1/2 and partially reduced pERK1/2
Cancer Res. 2023 Sep 15;83(18):3001-3012.
KPC210-MR cells
1 µM
48 hours
To investigate the ferroptosis inhibition mechanism in MRTX1133-resistant cells, results showed that increased MGST1 expression led to ferroptosis inhibition.
Mol Med. 2024 Nov 5;30(1):199.
AsPC1-MR cells
1 µM
48 hours
To investigate the ferroptosis inhibition mechanism in MRTX1133-resistant cells, results showed that increased MGST1 expression led to ferroptosis inhibition.
Mol Med. 2024 Nov 5;30(1):199.
KPC210 cells
1 µM
48 hours
To investigate the anti-tumor effect of MRTX1133 on KRASG12D-mutated PDAC cells, results showed that MRTX1133 induced ferroptosis.
Mol Med. 2024 Nov 5;30(1):199.
AsPC1 cells
1 µM
48 hours
To investigate the anti-tumor effect of MRTX1133 on KRASG12D-mutated PDAC cells, results showed that MRTX1133 induced ferroptosis.
Mol Med. 2024 Nov 5;30(1):199.
PK-59
5 nM
48 hours
To evaluate the effect of MRTX1133 on KRASG12D-mutant pancreatic cancer cells, results showed reactivation of AKT phosphorylation
Mol Oncol. 2025 Feb;19(2):377-390.
PANC-1
5 nM
48 hours
To evaluate the effect of MRTX1133 on KRASG12D-mutant pancreatic cancer cells, results showed phosphorylation of ERK and STAT3 was inhibited
Mol Oncol. 2025 Feb;19(2):377-390.
KP-4
4 nM
48 hours
To evaluate the effect of MRTX1133 on KRASG12D-mutant pancreatic cancer cells, results showed KP-4 had slight intrinsic resistance to MRTX1133
Mol Oncol. 2025 Feb;19(2):377-390.
SUIT-2
5 nM
48 hours
To evaluate the effect of MRTX1133 on KRASG12D-mutant pancreatic cancer cells, results showed MRTX1133 inhibited phosphorylation of ERK and STAT3
Mol Oncol. 2025 Feb;19(2):377-390.
AsPC-1
35 nM
72 h
To evaluate the synergistic effects of MRTX1133 with various drugs and identify potential combination therapies
Mol Oncol. 2025 Feb;19(2):295-310.
MRTX1133 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Subcutaneous tumor model
Intraperitoneal injection
30 mg/kg (twice daily)
Twice daily until study endpoint
Venetoclax enhanced the efficacy of MRTX1133 in vivo, leading to tumor growth suppression and partial tumor regression.
Cancer Res. 2024 Nov 4;84(21):3629-3639.
Mice
PDAC mouse models
Intraperitoneal injection
6 mg/kg and 12 mg/kg
Once daily for 10 days
Combination of MRTX1133 and afatinib led to tumor regression and prolonged survival
Cancer Res. 2023 Sep 15;83(18):3001-3012.
Mouse
KPC allograft model
Intraperitoneal injection
30 mg/kg/day
Once daily until tumor volume reached approximately 1500 mm3
Evaluate the antitumor efficacy of MRTX1133 alone or in combination with PGG
Cell Rep Med. 2025 Feb 18;6(2):101966
Nude mice
Subcutaneous injection of AsPC1-MR cells
Intraperitoneal and intratumoral injection
1 mg/kg
MRTX1133 once daily, PKF-118-310 twice a week for 19 days
To investigate the inhibitory effect of combined treatment with PKF-118-310 and MRTX1133 on MRTX1133-resistant tumors, results showed that the combination significantly suppressed tumor growth and induced ferroptosis.
Mol Med. 2024 Nov 5;30(1):199.
BALB/cAJcl Foxn1nu mice
SUIT-2 xenograft model
Oral
0.5 mg/kg
Once daily for 21 days
To evaluate the antitumor effect of MRTX1133 alone and in combination with trametinib and fedratinib, results showed the three-drug combination therapy significantly inhibited tumor growth
Mol Oncol. 2025 Feb;19(2):377-390.
Mouse
HG-PMP xenograft mouse model
30 mg/kg
MRTX1133 significantly inhibited tumor growth, reduced cell proliferation, increased apoptosis, and decreased the activity of MAPK and PI3K/AKT/mTOR signaling pathways
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