RAS-RAF-MEK-ERK: A full line of classic tumor signaling paths.

RAS-RAF-MEK-ERK, based on in-depth research in recent decades, has become a classic tumor signaling pathway, which is closely related to the occurrence of multiple cancer species, and for the key target of this pathway, has successfully marketed a number of drugs, in the study of drug pipeline has also become a gradient distribution, gradually become a clear mechanism of action and targeted drug-rich signaling pathway.
1, MAPK and RAS-RAF-MEK-ERK Signal Paths Before introducing the RAS-RAF-MEK-ERK path, here's a brief introduction to MAPK.
MAPK, or fissure active protein kinase, whose signaling path can transfer extracellular signals into cells and conduct cell signals through three-stage kinase cascading (MAPKKK-MAPKK-MAPK) to regulate biological functions such as cell proliferation, differentiation, apoptosis, inflammatory response, and vascular development.
1.1 MAPKs signal conduction paths in mammalian bodies (Photo: doi:10. 11665/j. issn. 1000-5048. 20200302) RAS-RAF-MEK-ERK is the most in-depth study of mapks above! First of all, the RAS protein with GTPase activity is activated by the upstream RTK and so on, the activated RAS activates the RAF by binding to the N-side domain of the RAF, the activated RAF can further bind to the downstream MEK protein and then activate the MEK, the activated MEK further activates the downstream sole substrate ERK, and finally activates the ERK into the nucleation of the cell, which in turn causes a series of physiological bioactivation reactions.
1.2 MAPK pathway activation and feedback regulation (Source:) The relationship between signaling pathways and tumors As described above, Ras is a GTP binding protein that has been an important target for cancer research to date.
three isomer forms exist in the human body: H-Ras/K-Ras/N-Ras, which have 85% amino acid ionospheric sequences and are associated with tumors.
K-Ras has a wide range of expressions and is highly associated with pancreatic catheter cancer, with K-Ras mutations found in more than 90% of pancreatic catheter adenocarcinomas, and in melanoma, RAS mutations are nearly 28%, of which N-Ras is the main mutant (93%).
and B-Raf, one of three subsypes in the RAF protein family of serine-suline protein kinases (A-Raf, C-Raf/Raf-1), are the most common mutation types in RAF proteins, commonly found in melanoma, thyroid cancer, and colorectal adenocarcinoma.
RAF further activates MEK, MEK1/2 is not as common as B-Raf and RAS mutations, but it is precisely because it is located in the lower reaches of RAS and RAF with relatively high mutation rates, making it an ideal therapeutic target.
clinical applications, the target inhibitor is also mainly used for melanoma and lung adenocarcinoma.
Figure 2.1: RTK-RAS-RAF mutation incidence of different malignant solid tumors (Source: ) Although the development of important-point varieties K-Ras is very important, so far there have been no varieties on the market, the clinical stage of the variety is not particularly many The more representative varieties are Salirasib of Ono Pharmaceuticals (non-small cell lung cancer, pancreatic cancer), and Prolexys' PRLX-93936 (to adapt to multiple myeloma).
RAF inhibitors, especially B-Raf/C-Raf inhibitors, have been marketed in several drug varieties, but are mostly multi-target multi-kinase inhibitors, such as sorafinib, peropani, velofinib, rigoffinib, darafinib, Encorafenib, etc.;
Domestic investment in this target is relatively small, but the well-known innovative pharmaceutical company Baiji Shenzhou has two varieties into the clinic, namely, Lifirafenib in phase II clinical stage (to adaptive melanoma, colorectal cancer and non-small cell lung cancer), and BGB-32 in phase I clinical phase 45-MBP (to-adapt melanoma, colorectal cancer, non-small cell lung cancer);
Table 3.1 B-Raf/C-Raf Target-related globally marketed drug MEK inhibitors, there are currently several drugs on the market, clinical adaptation is mainly melanoma, such as trametinib, selumetinib, etc.;
domestic development of MEK inhibitors, Hengrui, Tianqing, cornerstones have varieties in the column, but are in the early stages of clinical development.
Table 3.2 MEK Target-related globally marketed drug ERK inhibitors, although no inhibitors have been officially approved for the market, but there are already some small molecule inhibitors in the clinical research stage, the highest stage is Clinical Phase III, for Honokiol (to adapt to gum disease).
The development of ERK inhibitors in China is mainly HH-2710 (a malignant tumor with abnormal MAPK signaling pathline) developed by the drug, and BPI-27336 developed by Beida Pharmaceuticals (with colorectal cancer, pancreatic cancer, lung cancer, liver cancer, stomach cancer, melanoma, etc.).
Summary, that is, for the cancer classic signaling path mapK to "RAS-RAF-MEK-ERK" targeted anti-cancer drug current development status, although not every important signal target has a drug market, but no matter from the proportion of its listed drugs, current research, as well as the domestic layout of the signaling path product, can prove its importance to control the development of tumor malignancy.
and in view of the current overall state of the research varieties, there is still a lot of room to continue to develop, very worthy of domestic scientific research work for this signal path investment! Resources: 1.Imperial, R., Seminars in Cancer Biology (2017). 2. Journal of China Pharmaceutical University 2020,51 (3):260 - 269.doi:10. 11665/j. issn. 1000 -5048. 20200302 3.Cellular Signalling 67 (2020) 109497. 4. Acta Pharmaceutica SinicaB2018; 8 ( 4):552–562. 5. Pharmaproject/Cortellis Date.