c-Met inhibitors enter harvest period: 2 milestone drugs approved dozens of domestic drugs clinical.

The penodrug mad 2020, c-Met inhibitors into the harvest period! After the multi-target development of the listed drugs ketinib and cabotinib, Merck developed the high-selective c-Met inhibitor Tepotinib, Novartis developed a high-selective c-met inhibitor Capmatinib was approved for listing in Japan and the United States in the first half of 2020! At the same time, the domestic drug development for the target has dozens of varieties into the clinical, Volitini has been developed to the NDA stage! C-Met's therapeutic value in the field of oncology is about to be more comprehensively validated in clinical practice.
1, c-Met/HGF targets introduce the primary cancer gene Met code c-Met (cellular-mesenchymal epithelial transition factor) is a highly binding receptor tyrosine kinase, belonging to the RON subnational, is the only known receptor of hepatocellular growth factor (HGF).
in NSCLC, which accounts for 80%-85% of lung cancer, 3%-5% of patients develop met gene amplification or exon 14 mutations.
here to explain the above two concepts: 1) MET14 exon mutation, namely, MET14 exon coding part of the JM domain Y1003 and c-CblE3 ubiquitin connecting enzyme binding site missing, resulting in ubiquitin reduction, so that MET continued activation;
drug development is also mainly concerned with the above two points.
Figure 1.1: Structural domain characteristics of C-MET and its ligand HGF (Picture: NATURE REVIEWS. CLINICAL ONCOLOGY) HGF and c-Met transiocitia binding, will induce c-Met phosphorylation, in the C-side multi-functional region to collect a variety of cytokines, such as GAB1 (growth factor receptor binding protein-1), GAB2, etc., further attract SHP2, PI3K and other molecules binding here, thereby activating RAS/MAPK, PI3K/AKT, JAKKT," etc.
Figure 1.2: c-Met/HGF activation pathways and some inhibitors (Image source: Cancer Treatment Reviews.) 2, Global Drug Development Statistics through database query, currently for c-Met/HGF target development, there are currently 4 drugs listed, respectively, the 2011 listing of Crizotinib, 2012 listed Cabonoib Cabozantinib, Capmatinib and Tepotinib in the first half of 2020, the most non-small cell lung cancer; among them, cortinib and Cabotinib are multi-target drugs, which were not initially targeted at c-Met, while Capmatinib and Tepotinib are relatively authentic, highly selective c-Met inhibitors! The NDA phase of the drug, mainly Volitinib, developed by the domestic pharmaceutical company Hutchison Whampoa, and authorized to AZ for global development in 2011, is of great concern.
phase III clinical phase of the varieties, mainly Tivantinib, Refanalin, Sitravatinib, it is worth mentioning that Refanalin, which is not anti-tumor drugs, indications for "post-transplant functional delay recovery", which to a certain extent to the development of c-Met inhibitors to increase an important research direction.
Phase II/I clinical representative of the drug , 50 , not to mention here .
Table 2.1: Global c-Met Inhibitor Statistics (Clinical Phase III) 3, Domestic Drug Development Statistics as mentioned above, the fastest progress for the development of target c-Met is Volitinib, developed by Hutchison Whampoa, authorized in the early years of AstraZeneca for global drug development, has now entered the NDA stage, indications developed as non-small cell lung cancer.
phase II varieties currently have 4, respectively, Shanghai Green Valley / Shanghai Drug Institute's Gu metinib, Sichuan Hengkang Group's Boretini, Dongsun Medicine's Ningatini, and Zhengda Qing's AL-2846;
and enter the phase I clinical species are relatively large, there are more than ten, the specific varieties see the table below.
Table 3.1: Domestic c-Met Inhibitor Development Statistics 4, domestic and foreign c-Met inhibitors on behalf of the fda-approved high-selective c-met inhibitor - Capmatinib May 2020, FDA approved Novartis c-met inhibitor Tabrecta (capinmatib) listing for the treatment of locallate or metex 14 patients with mutations in NSCLC patients, including treatment.
Tabrecta is the first and only fda-approved treatment specifically for METex14 mutant metastatic NSCLC! As mentioned above, meTex14 mutation late NSCLC is a very poor prognosis of lung cancer, there is no clear treatment plan.
in the United States, about 4000-5000 patients are diagnosed with METex14 metastatic NSCLC each year; Figure 4.1: Capmatinib's selectivity of some human kinases and mutant kinases (Photo: FDA website information) domestic NDA variety - Volitinivolitinib, developed by Hutchison Whampoa, is a highly selective c-Met inhibitor (nM) level), and through structural optimization, greatly improve the c-Met inhibitor nephrinotoxicity problems, in addition to the main indications of non-small cell lung cancer, clinical development of renal cell cancer (Phase III), colorectal cancer (Phase II), stomach cancer (Phase II), prostate cancer (Phase II), etc.
since the application for clinical, has been nearly 8 years, and in 2011, authorized to AZ co-development, and AZ for the development of the species is also a large area spread! Table 4.1: Volitinib Global Clinical Trials Partial Registration Information 5, Summary, is the main development statistics for current global c-Met inhibitors.
the two c-Met inhibitors approved in the first half of 2020, the impact on drugs in this field will undoubtedly be a milestone, the target c-Met is important to the field of cancer, and will soon be known! And the development of highly selective targeted drugs further proves the maturity of drugs in this field.
with the follow-up drug in the clinical process of the continuous verification of the target, I believe that the clinical needs of this field will be greatly satisfied, and for the domestic market of the target drug, c-Met inhibitor rapid development, whether for pharmaceutical companies or patients are urgent needs, so as to solve the unmet clinical needs! Reference: 1. NATURE REVIEWSS . . . CLINICAL ONCOLOGY. doi: 10.1038/nrclinonc.2017.402.Targeting The HGF/MET Axis in Cancer Therapy: Challenges in AndErAndes for Improv. Frontiers in Cell and Developmental Biology, 2020, 8.3.MET puts for the targeted therapy of EGFR TKI-rhoit lung cancer . Journal of Hematology and Oncology, 2019, 12 (1): 63.4. Nature Reviews Cancer, 2018, 18 (6): 341-358.5. European Journal of The Post. DOI: 10.1016/j.ejmech.2015.12.0166.Cancer Treatment Reviews.7.Newport/ProjectS Date8.FDA.