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Fibroblast growth factor receptors (FGFRs) belong to the family of receptor tyrosine kinases (RTKs), which regulate the dynamic balance of various physiological activities such as cell proliferation, growth, migration and differentiation
.
Disturbance of FGFRs signaling pathway or activation of oncogenes may lead to carcinogenesis, tumor cell proliferation and anti-apoptosis
.
Aberrations of FGFRs are widely distributed in all malignant tumors, including urothelial cancer, cholangiocarcinoma, breast cancer, endometrial cancer, squamous epithelial cancer, etc.
At present, three FGFR inhibitors have been approved for marketing, namely Erdafitinib, Infigratinib, and Pemigatinib, and more FGFR inhibitors are under development in the future
.
Next, the author will focus on the binding mode of FGFR inhibitors and their main differences
PD173074 (left in Figure 2) is the first reported pyridine [2,3-d] pyrimidine selective FGFR small molecule inhibitor
.
From the eutectic structure with FGFR1 (Figure 2 right), it can be found that the dimethoxybenzene ring of PD173074 occupies the hydrophobic pocket in the ATP binding pocket through van der Waals interaction, and one of the methoxy groups forms a hydrogen bond with Asp641
Erdafitinib (Figure 3) is a potent FGFR inhibitor based on quinoxaline fragments
.
From the point of view of molecular structure, it can be regarded as a modification of PD173074 (Figure 4 left): The dimethoxybenzene ring in PD173074 moves to the N atom of urea.
The core of Infigratinib (Figure 1) is quite different from PD173074: the use of intramolecular hydrogen bonds to replace the originally rigid six-membered ring (pseudo six-membered ring strategy) (Figure 5 left)
.
This design idea is also explained in Novartis's article
The Pemigatinib reported in the literature is modified from a multi-target small molecule (Figure 6 left)
.
If we compare Infigratinib and Pemigatinib carefully, we can find that Pemigatinib is actually a variant of Infigratinib (Figure 6 right): the original "pseudo six-membered ring" is connected by physical bonds, and the aniline at the tail is incorporated into the core.
CH5183284/Debio 1347 is an FGFR inhibitor optimized by Japanese Chugai Pharmaceutical through high-throughput screening and is currently in clinical phase I/II (Figure 8 left)
.
CH5183284 is somewhat different from other FGFR inhibitors.
Futibatinib (TAS-120) is an irreversible FGFR inhibitor developed by Japan's Dapeng Pharmaceutical
.
On April 2, the US FDA has granted a breakthrough therapy designation for the treatment of locally advanced or metastatic cholangiocarcinoma after treatment
There are many small FGFR molecules currently in clinical practice.
This article is only an overview of the classic binding mode
.
The above-mentioned parts are only personal opinions, and may not be consistent with actual R&D ideas
.
Recently, CDE’s "Clinical Value-Oriented" guiding principle has caused heated discussions, and the development of Me-too drugs has been questioned for a while
.
The author also believes that the practice of blindly and simply changing the substituents in order to break the patent does need to be corrected, but there is still some me-too that has clinical value
.
For example, most of the above-mentioned FGFR inhibitors are derived from the binding mode of PD173074
.
Innovation itself is to stand on the basis of predecessors.
For some high-quality targets, targeted development of me-too with different clinical advantages can not only prevent FIC from monopolizing the market, but also provide different patients.
Individualized drug support can also effectively reduce the company's research and development costs
.
references:
[1] Moosa Mohammadi et al.
Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.
The EMBO Journal 1998, 17, 5896–5904.
[2] Christopher W.
Murray et al.
A successful collaboration between academia, biotech and pharma led todiscovery of erdafitinib, a selective FGFR inhibitor recently approved by the FDA.
MedChemComm 2019, 10, 1509–1511.
[3] Harshnira Patani et al.
Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.
Oncotarget.
2016, 7, 24252–24268.
[4] Vito Guagnano et al.
Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino] -pyrimidin-4-yl)-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase.
J.
Med.
Chem.
2011, 54, 7066–7083.
[5] Liangxing Wu et al.
Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.
J.
Med.
Chem.
2021, 64, 10666−10679.
[6] Yoshito Nakanishi et al.
The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor.
Mol Cancer Ther.
2014, 13, 2547-2558.
[7] Maria Kalyukina et al.
TAS-120 cancer target binding; defining reactivity and revealing the first FGFR1 irreversible structure.
ChemMedChem.
2019, 14, 494-500.
