A list of research on the gold-FGFRs inhibitors.

FGFRs is a typical class of receptor tyrosine kinases (receptor tyrosine kinases, RTKs), whose family consists of FGFR1, FGFR2, FGFR3 and FGFR4 receptors, all of which are composed of three parts: the extracellular region, the transmembrane region and the intracellular tyrosine kinase region.
FGFR's high expression, mutation, etc. lead to abnormal activation of its signaling pathways, and are closely related to the development of a variety of diseases, including lung cancer, stomach cancer, breast cancer, colorectal cancer, chronic granulocytic leukemia, bile duct cancer, cerebroblastoma, cartilage sarcoma, lipoma, bladder cancer and so on.
The distribution of FGFRs targets in different tumors has been studied by FGFRs target inhibitors for FGFRs small molecule inhibitors in the 1990s, later than in other similar targets such as endothelial growth factor receptors (VEGFR) and epidermal growth factor receptors (EGFR) families.
depending on the protein binding sites of inhibitors and FGFR, they can be divided into two types, the first is to inhibit the catalytic activity of FGFR or tyrosine self-phosphorylation, which is a small molecular compound by targeting the tyrosine kinase domain in the membrane.
another type is the target FGFR extra-membrane immunoglobulin domain, competitively binding fGFR outer region with FGFs, blocking FGF-FGFR binding and pathway activation.
Although the listed multi-target tyrosine kinase inhibitor (TKIs) can be used to treat tumors with FGFRs mutations, FGFR is not its primary target (Table 2).
such as ponatinib for the treatment of leukemia, its main targets are Abl, PDGFR alpha, VEGFR2, FGFR1.
currently available for selective suppression of FGFRs targets, only the available drug is erdatinib Balversa (erdafitinib).
, the FDA has officially announced the accelerated approval of the listing of The FGFR2 inhibitor pemigatinib developed by Incyte for the treatment of patients with advanced biliary cancer with FGFR2 gene fusion or other rearrangement types.
Table II, the listed tyrosine kinase inhibitor TKIs FGFRs target spent on FGFR target suppression at the drug research currently, there are several FGFRs inhibitors in clinical research stage, the following is a brief introduction.
Pemigatinib Pemigatinib is the first targeted new drug for bile duct cancer.
the drug is a strong selective oral inhibitor for FGFR subtype 1/2/3, which has been shown in previous clinical studies to have selective pharmacological activity on tumor cells with mutations in the FGFR gene.
the effective ORR of patients with second-line treatment of bile duct cancer was 35.5%, and the disease control rate was 82%.
recently, the FDA officially announced the accelerated approval of incyte's development of the FGFR2 inhibitor pemigatinib, treatment of FGFR2 gene fusion or other re-type patients with advanced biliary cancer, marking the end of the era of chemotherapy for bile duct cancer.
In addition to the second-line treatment of bile duct cancer patients, Pemigatinib also conducted a first-line study called FIGHT 302III, which is a head-to-head comparison, Pemigatinib and Gisitabin combined with the first line of the treatment of non-surgical excision or metastatic companion FGFR2 resection of advanced bile cancer patients.
not long ago, Cinda Bio announced that the first patient in China had completed the first administration of pemigatinib.
the purpose of this study is to assess the effectiveness and safety of pemigatinib in patients with advanced bile duct cancer in China who have previously received at least first-line systemic therapy, gene fusion of fibroblast growth factor receptor 2 (FGFR2) gene fusion or re-arrangement, and the results of this study will be used in the application of migpeatinib for new drug marketing (NDA) in China.
Infigratinib (BGJ398) In January 2018, BridgeBio announced that it had obtained authorization from Novartis to develop a new anti-cancer drug, infigrat (BGJ398), and that its subsidiary QED Therapeutics was responsible for promoting the development of this powerful selective tyrosine kinase receptor FGFR inhibitor.
Infigratinib is an oral administered, ATP competitive FGFR1-3 tyrosine kinase inhibitor used to treat FGFR-driven diseases, including bile duct cancer, urinary skin cancer (bladder cancer) and inadequate cartilage in children.
was granted fast-track status by the FDA in early January 2020.
currently, a clinical phase III trial trial trial for first-line treatment of Infigratinib for bile duct cancer (CCA) is under way.
the purpose of this study is to compare the efficacy and safety of patients with local late or metastatic bile duct cancer who are treated with the first line of oral Infigratinib and standard-care chemotherapy (Gisitabin combined cisplatin) for FGFR2 gene fusion/translocation.
subjects were treated at random 2:1 in Infigratinib or Gisitabin combined cisplatin.
another phase III clinical trial, PROOF 302 (NCT03773302), is currently under way.
this is a multicenter, double-blind, randomized, placebo-controlled study designed to assess the efficacy of giving oral Infigratib as an auxiliary treatment after surgery in adult patients with invasive urinary skin cancer and FGFR3 gene changes (mutations, gene fusion or rearrangement).
Rogaratinib (BAY1163877) Rogaratinib (BAY 1163877) is an efficient, selective small molecule pan-FGFR (FGFR1-4) inhibitor developed by Bayer Ag.
Rogaratinib is currently undergoing several clinical trials as monotherapy (NCT03762122, NCT03410693) and joint immunocheckpoint inhibitors (NCT03473756) or targeted therapy (NCT03517956, NCT03088059).
, NCT03410693 has entered clinical phase III studies, evaluated the efficacy and safety of rogaratinib in patients with FGFR-positive, locally advanced or metastatic urinary tract skin cancer, and proved that rogaratinib is better than chemotherapy for the extension of total survival.
2019 ASCO summary contains data from rogaratinib (J Clin Oncol 37:15s, 2019, suppl; abstr e20661).
study included 40 patients with advanced NSCLC who were positive in mRNA with FGFR.
ORR was 5.6% (one reaction lasted more than 16 months) and the DCR was 64%.
drug safety, Rogaratinib is tolerable, mostly light and moderate AE.
Futibatinib (TAS-120) Futibatinib (TAS-120) is an oral bioavailability, highly selective, and irreversible FGFR inhibitor developed by Taiho Corporation of Japan.
Futibatinib (TAS-120) combines with the highly conservative P-ring cysteine residue in FGFR's ATP pocket, and performs high specificity for wild FGFR1/2/3/4 and certain FGFR2 kinase domain mutations, which are second-generation FGFR inhibitors.
August 2019, Cancer Discovery Magazine (Cancer Discovery 2019, 9, 1064.) reported on new advances in resistance to tAS-120.
4 patients with a generation of treatment, BGJ398, who were treated with a single generation of drugs, but later had resistance to bile duct cancer, received TAS-120 treatment, 2 patients showed objective remission, and 2 patients were stable and had a control rate of 100%.
2 of these patients with effective PFS for more than a year showed good prospects.
currently, Futibatinib's Phase III FOENIX-CCA3 (NCT04093362) study is evaluating the effectiveness and safety of Futibatinib's first-line treatment of patients with advanced bile duct cancer (CCA) with FGFR 2 gene rearrangement.
in addition, Futibatinib's Phase II Basket Study (NCT04189445) is evaluating the effectiveness and safety of Futibatinib's treatment of advanced solid tumors with FGFR gene abnormalities.
AZD4547 AZDD4547 is a selective FGFR inhibitor with an IC50 value of 0.2nM/2.5 nM/1.8nM, weak activity for FGFR4, VEGFR2 (KDR) and little activity on IGFR, CDK2 and p38.
AZD4547 is mainly in clinical trials of lung scale cancer and stomach cancer.
15 patients with pneumoscoatomeuunding of the FGFR1 gene received AZD4547 treatment, 1 patient was objectively relieved and 2 patients were stable for more than 3 months, and another enrolled in a small-scale clinical trial of 43 patients with advanced lung scale cancer, 2 patients with objective remission, with a median total survival time of 7.5 months.
2018 ASCO annual meeting announced the therapeutic effect of AZD4547 in FGFR mutation/amplification/fusion solid tumor, and the results showed overall ORR 9.5%, SD 47.6%, and median PFS 3.8 months.
at present, patients with malignant pleural mesothelioma (MPM) relapse after first-line chemotherapy, and there is no effective treatment.
February 2020, Lung Cancer published a single-center, open-label, single-arm phase II study of AZD4547 to assess the efficacy of AZD4547 as a second- or third-line treatment of malignant pleural mesothelioma (Lung Cancer 2020, 140, 87-92. the main endpoint of
is a six-month progression-free survival period (PFS6).
the results showed that 3 (12%) of the 24 patients showed no progress at 6 months, indicating that AZD4547 did not show efficacy in MPM patients who progressed after treatment with first-line platinum chemotherapy, and the trial was terminated.
November 2019, Shanghai and Yupharma announced a global exclusive licensing agreement with AstraZeneca for the development and commercialization of the innovative drug AZD4547.
obtained a license for the exclusive development, production and commercialization of AZD4547 worldwide under the agreement.
AstraZeneca will receive the corresponding down payment, milestoneand and sales commission.
other FGFRs inhibitors in clinical development are shown in Table 3. the development of FGFR inhibitors in clinical phase of
table III The development of FGFR inhibitors offers hope for targeted treatment in FGFRs-driven tumor patients.
development and listing, such as Pemigatinib, is a landmark outcome of targeted treatment for bile duct cancer.
However, the research of FGFR inhibitors also faces many challenges.
such as the generation of drug resistance, dose restrictions caused by the toxicity of inhibitor-type drugs, and so on.
this is also the future Research and Development of FGFR inhibitor drugs to solve the key issues.
the irreversible combination of TAS-120 to FGFR overcomes some of the problems of drug resistance.
currently, many pharmaceutical research and development companies have a layout of FGFRs inhibitor circuit, I believe that FGFR inhibitor drugs can bring more hope to cancer patients.
References 1.Cells 2019, 8, 614. 2. Clin Cancer Res 2020,26,764. 3.Eur J Med Chem 2020, 186, 111884. 4.