K-Ras protein is a kind of GTPase. Specifically, it is a kind of enzyme that converts nucleotide guanosine triphosphate (GTP) to guanosine diphosphate (GDP). In this way, the K-Ras protein acts like a switch. Besides, KRAS is the most frequently changed homotype in NSCLC cases with RAS mutation. Moreover, KRAS is one of the most common carcinogenic driving mutations in non-small cell lung cancer (NSCLC).

Furthermore, due to the structural and biochemical characteristics of the KRAS protein, it is challenging to determine an effective therapy for KRAS mutant NSCLC. Firstly, the surface of the KRAS protein is too smooth to bind with other small molecule inhibitors. Secondly, the high-affinity binding between GTP and KRAS protein is difficult to break. In addition, there is almost no structural difference between wild-type and mutant KRAS. The significance of KRAS mutation is the current status of potential therapeutic targets with great prospects. Importantly, G12C mutation in the KRAS gene can be directly inhibited by the newly unearthed switch II pocket. The effect of KRAS G12C mutation on the prognosis of metastatic colorectal cancer (mCRC) is very important for the development of new clinically effective drugs. Here, we will introduce a potent KRAS G12C inhibitor, BI-0474.

BI-0474 is a Potent KRAS G12C inhibitor.

At first, BI-0474 is a potent KRAS G12C inhibitor with an IC50 value of 7.0 nM for the GDP-KRAS::SOS1 protein-protein interaction. Particularly, BI-0474 exhibits good anti-proliferative activity against NCI-H358 cells carrying the G12C mutation. Obviously, BI-0474 also shows good anti-tumor activity in non-small cell lung cancer xenograft models.

Secondly, BI-0474 with 1-10,000 nM for 3 days shows the potent antiproliferative activity of 26 nM on NCI-H358 cells carrying a G12C mutation. Additionally, BI-0474 with 40 mg/kg by i.p. shows anti-tumor efficacy. At the same time, BI-0474 has pharmacodynamic biomarker modulation in an NCI-H358 cell line-derived non-small cell lung cancer xenograft mode.

Finally, BI-0474 is a potent KRAS G12C inhibitor.


Bröker J, et al. J Med Chem. 2022 Oct 27.