As a promising target, FGFR4 is attracting intensive pharmaceutical and academic attention for developing novel target therapy against cancers driven by FGFR4. The three strategies that have been developed to target FGFR4 include neutral antibodies, antisense oligonucleotides, and small molecule inhibitors. Not surprisingly, multi-targeted tyrosine kinase inhibitors (mTKIs) can be used to inactivate FGFR4 by disrupting ATP binding in its TK domains. The anticancer activity of many mTKIs, including lenvatinib and ponatinib, has been tested on FGFR-driven solid tumors in animals or in clinical trials. However, the limited selective activity of mTKIs on FGFRs induces less efficiency and increases side effects in these treatments. Therefore, pan-FGFR inhibitors are developed and are being evaluated in clinical trials to treat cancers driven by abnormal FGFR pathways. Other inhibitors in this category include ATP-competitive inhibitors NVP-BGJ398 and AZD4547, ATP-binding pocket inhibitor LY2874455, and FGFRs-FIIN-3. At present, FGFR blockers, such as multi-kinase inhibitors, specific FGFR inhibitors, and FGF ligand traps are being tested in clinical trials.
Small molecule inhibitors of FGFR tyrosine kinase, selective or nonselective, are under clinical evaluation, although mainly in the early stages of trials. Efforts are being made for increasing the selectivity to the intracellular ATP-binding domain of the receptor to minimize the toxicity. AZD4547 is another TKI, which has shown strong activity against FGFR-3, yet weaker activity against FGFR4. The development of non-selective TKI-targeting FGFRs recently shown to be very successful in preclinical studies. Some of these inhibitors have known to be passed the phase I trial showing encouraging results in terms of safety and tolerability. Less number of studies is found to be in clinical trials. The drugs that are in clinical trails include Rogaratinib by Bayer, Ensartinib by Betta Pharmaceuticals, Roblitinib (FGF401) by Novartis, Lenvatinib by Esai Co Ltd, Nintedanib by Boehringer Ingelheim, FGF19 by Genentech, and ponatinib hydrochloride by Ariad pharmaceuticals for malignant neoplasm. BLU-554, a potent fibroblast growth factor receptor 4 (FGFR4) inhibitor is a new drug that is approved by Neil Bifulco, Lucian V. Dipietro, Brian L. Hodous, Chandrashekar V. MIDITURU.
A long series of evidence is said to be pointing towards the expectation that deregulated FGFRs can work as driving oncogenes in several types of tumor. The FGFRs/FGFs (Fibroblast growth factor receptors / Fibroblast growth factors) axis is offering interesting molecular targets to be pursued in clinical development. FGFR is an already established breast cancer oncogenic driver involved in various mechanisms leading to the formation of vessels, tumor growth and avoidance of apoptosis. The therapeutic strategies have been implemented in order to inhibit FGFRs. In fact, several anti-FGF/FGFR therapies have been tested at phase I and II clinical trials.
This Pipeline research report segments the Fibroblast Growth Factor Receptor inhibitors pipeline on the basis of therapies employed (combination therapy, and monotherapy + combination therapy), therapeutic modality (small molecules, and unknown), RoA (oral and unknown), drugs under development (discovery, pre-clinical, phase I, phase I/II, phase II, and phase III), and recruitment status (recruiting, active not recruiting, enrolling by invitation, and undisclosed).
The Key players analyzed in Fibroblast Growth Factor Receptor 4 (FGFR4) Inhibitors pipeline include Ionis Pharmaceutical, H3 BiomedicineInc, Daiichi SankyoInc, Blueprint MedicinesCorp., IncyteCorporation, Genosco, AstraZeneca, and others.
The report highlights information on emerging companies with potentially disruptive technologies and new market entrants.
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