Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation[1].
BI-3406 is an orally active, highly potent and selective between KRAS and Son of Sevenless 1 (SOS1) interaction inhibitor (IC50: 6 nM), with anticancer activity. BI-3406 does not block the interaction of KRAS with SOS2 but elicits activity on a broad panel of KRAS oncogenic variants, including all major G12 and G13 oncoproteins. In KRAS-dependent cancers, BI-3406 potently reduces the formation of GTP-loaded KRAS, and inhibits MAPK pathway signaling. Down-modulation of this signaling cascade by BI-3406 in KRAS G12 or G13 mutant cells effectively limits cell proliferation[2]. BI-3406 inhibits SOS1 catalyzed formation of GTPKRAS in KRAS-mutant cells (IC50 = 83-231 nM), inhibits downstream signaling (pERK IC50 = 17-57nM), and inhibits proliferation in anchorage-independent 3D growth assays (IC50 = 16-52 nM) in a range of KRASmutant cells[1]. BI-3406 is an orally bioavailable compound and single administration was sufficient to reduce RAS-GTP and pERK levels in A549 xenograft tumors over a period of 24 hours and 7 hours, respectively. At a dose of 50 mg/kg bid, relevant levels of unbound exposures are achieved for the first 12 hours, when compared to unbound IC50 levels in A549 cells. In MIA PaCa-2 tumor bearing mice, twice daily compound treatment with 50 mg/kg BI-3406 resulted in pathway modulation over a period of up to 10 hours[3].
BI-3406 细胞实验
Cell Line
Concentration
Treated Time
Description
References
K562 cells
10, 100, 1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
NCI-H358
500 nM
72 hours
Evaluate the antiproliferative response of BI-3406 in combination with adagrasib
Nat Cancer. 2024 Sep;5(9):1352-1370.
SW837
1200 nM
144 hours
Evaluate the antiproliferative response of BI-3406 in combination with adagrasib
Nat Cancer. 2024 Sep;5(9):1352-1370.
6606PDA cells
10 µM
48 hours
To evaluate the synergistic inhibitory effects of BI-3406, trametinib, and BKM120 on the proliferation and cell death of 6606PDA cells. The results showed that the combination of these three drugs significantly reduced BrdU incorporation and synergistically induced cell death.
Cancers (Basel). 2024 May 16;16(10):1901.
NCI-H358 cells
1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
GP2d cells
1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
SW620 cells
1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
HPAF-II cells
1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
MIA PaCa-2 cells
1000 nmol/L
24 hours
To evaluate the degradation ability of SIAIS562055 on SOS1, results showed that SIAIS562055 significantly degraded SOS1 protein.
Cancer Res. 2025 Jan 2;85(1):101-117.
Bone marrow-derived macrophages
1 μM
4 hours
To evaluate the effect of BI-3406 on macrophage gene expression. Results showed that combination treatment significantly decreased Cxcl2 gene expression and increased IL6 and Cx3cr1 expression.
J Pharmacol Exp Ther. 2023 May;385(2):106-116.
BI-3406 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
NCI-H2122 and SW837 xenograft models
Oral
50 mg/kg
Twice daily for 16 days
Evaluate the antitumor effects of BI-3406 in combination with adagrasib
Nat Cancer. 2024 Sep;5(9):1352-1370.
Mouse
DhhCre;Nf1fl/fl mice
Oral gavage
50 mg/kg
Twice daily for 58 days
To evaluate the effect of BI-3406 alone or in combination with selumetinib on neurofibroma growth. Results showed that combination therapy significantly reduced tumor volume and cell proliferation and altered macrophage morphology and activation status in the tumor microenvironment.
J Pharmacol Exp Ther. 2023 May;385(2):106-116.
C57BL/6J mice
Pancreatic ductal adenocarcinoma (PDAC) model
Oral gavage
50 mg/kg (twice daily)
From day 4 to day 36, using a 5-days on/2-days off dosing scheme
To evaluate the efficacy and potential adverse side effects of the combination of BI-3406, trametinib, and BKM120 in a PDAC model. The results showed that the combinatorial therapy significantly reduced tumor weight in male mice but had a weaker effect in female mice. Additionally, the therapy showed a higher therapeutic response in male mice.
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