From multi-target to high-choice global FGFR inhibitor pipelines are beginning to take shape!

In recent years, FGFR targets and their inhibitors have been highly concerned in the field of tumors, from the coverage of multi-target drugs, to the development of highly selective pan-target inhibitors, to the deep digging of subtypes of high-selective inhibitors, FGFR targets have been confirmed.
and associated highly selective inhibitors, which have also been approved by the FDA in recent years.
with the advance of foreign FGFR highly selective inhibitor market, the target direction of the study has reached what extent? What is the scope of coverage of listed drugs? What stage is the development of this target drug in China? The author summarizes the following.
1, FGFR biological function introduced FGFRs, fibroblast growth factor receptors, is a class of classic RTKs, its family includes FGFR1, FGFR2, FGFR3 and FGFR4 four receptors, all by the extracellular region - trans-membrane region - intracellular tyrosine kinase region three parts.
FGFs in combination with FGFRs causes djuogenization, which causes multiple tyrosine residues in the tyrosine kinase region of the cell to be active from phosphate.
activated FGFRs activate their substrate PLC and signal bridging protein FRS2 through phosphate, and their substrates reactivate signal path paths such as PI3K/AKT, PKC, STATS downstream (typical tumor pathps).
1.1: FGF/FGFR signal path (Source: ) The high expression and mutation of FGFR lead to abnormal activation of its signaling path, which is closely related to the occurrence and development of various diseases.
tumor-related diseases are lung cancer, stomach cancer, liver cancer, breast cancer, colorectal cancer, chronic granulocytic leukemia, bile tube cancer, cerebroglioblastoma, cartilage sarcoma, lipoma, bladder cancer, etc.
is also associated with non-tumor diseases such as bone diseases (cranial early closure syndrome, Kallman syndrome, osteoporosis stunting, cartilage dysplocy), glandular dysplution, Blaschko line pigmentation spots in children, arthritis.
Figure 1.2: Distribution of common FGFR mutant cancers (Source: 2, FGFR inhibitors have been marketed since the discovery of the target, there have been several varieties of drugs, but most of them are multi-target drugs, and the initial "target-drug" The development is not primarily targeted at FGFR; the true highly selective FGFR inhibitor, Erdafitinib, which was approved by the FDA in April 2019, is the first FGFR selective drug for metastatic urethring skin cancer second-line treatment.
Erdafitinib, developed under the code name JNJ-42756493 and developed by Jansen, is an effective oral pan-FGFR inhibitor;
April 2020, another highly selective FGFR inhibitor, Pemigatinib, developed by Incyte, was approved for the market.
Developed a number of good drugs, such as reedinin and barrettinib, and has established global partnerships with many large pharmaceutical companies.
Pemigatinib, the approved clinically adaptive disorder is "non-excisive localized advanced or metastatic bile tube cancer that has been treated in the past with FGFR2 fusion or other rearms".
it is worth mentioning that Cyda Bio and Incyte have reached a strategic partnership on the species for the commercial development of Pemigatinib's single and combined drugs in Greater China.
table 2.1 FGFR target related to listed drug statistics 3, FGFR inhibitor domestic related varieties development of domestic FGFR target development, similar to foreign development path, are based on multi-target development, gradually developed to highly selective varieties.
of these, the fastest-growing sovantinib developed for Hutchison Whampoa is an oral multi-target inhibitor targeting VEGFR, FGFR and CSF-1R, which is currently in the NDA phase.
for the development of highly selective FGFR inhibitors, according to the representative two varieties developed for Beida Pharmaceuticals, "BPI-17509" (adaptation is intended for advanced bladder cancer with FGFR3 gene mutation or fusion, with FGFR2) Gene fusion of bile tube cancer), "BPI-43487" (adaptation is intended to be used for fibroblast growth factor 19 amplification of hepatocellular carcinoma, bile tube cell carcinoma), and the highly-interested Nordsin Jianhua developed ICP-105 (adaptation in the treatment of liver cancer).
table 3.1 domestic FGFR target drug development statistics 4, the conclusion is not difficult to find, with the foreign highly selective inhibitors have entered the clinical and even approved listing, the domestic attention to the target has rapidly climbed, such as Bayda Pharmaceuticals, No cheng Jianhua and other innovative enterprises in the field of investment, but also a strong indication of the industry's optimistic direction.
And until now, the development of the target and its inhibitors is not as good as the development of EGFR and VEGFR inhibitors, expansion space still exists, especially the refinement of subtype drugs, the current need to further confirm its high selectivity, so the prospects of the drug in this direction is still very worthy of industry input and expectations.
: 1. Nature Reviews . . . Clinical Oncology 2. European Journal of Medicinal Chemistry3.The Breast4.Critical Reviews in Oncology/Hematology5.Pharmacology Research6.FGFR Inhibitor Research Progress 7. Pharmaproject database 8. Data.