FGFR4 is very popular!

Nowadays, the research scope of FGFR4 inhibitors is not only different from the choices of other kinases, but also the family subtype selectivity is deeply improved.

1.

In the following year, Pemigatinib developed by Incyte was approved to be marketed for use in adult patients with previously treated unresectable locally advanced or metastatic cholangiocarcinoma carrying FGFR2 gene fusion or other rearrangements.

In 2021, the FGFR1-3 selective tyrosine kinase inhibitor Infigratinib developed by QED Therapeutic was approved for marketing for use in previously treated unresectable locally advanced or metastatic bile ducts carrying FGFR2 gene fusion or other rearrangements.

Although the above-mentioned development companies are all foreign pharmaceutical companies, China's Cinda Biology and Liantuo Biology have participated in the development of Chinese rights and interests of related drugs

Figure 1.

2.

Figure 2.

The activation of FGFR4 receptor also requires a transmembrane protein β-Klotho, which interacts with FGFR4 to form a 1:1 complex to promote the binding between FGF19 and FGFR4

Figure 2.

(Image source: Pharmacology & Therapeutics 2020)

3.

Another test proved that after breeding FGF19 transgenic mice that knocked out FGFR4, it was found that only FGFR4 wild-type mice can develop hepatocellular carcinoma

Figure 3.

(Image source: Journal of Hepatology 2021)

In foreign countries, the clinical indications of FGFR4 have focused on breast cancer
.
For example, Pharmacology & Therapeutics (2020) published an article "FGFR4: A promising therapeutic target for breast cancer and other solid tumors".
The article pointed out that breast cancer is the most upregulated type of cancer.
Compared with normal tissues, FGFR4 is about 30%.
It is overexpressed in% of breast tumors, and has a significant effect in endocrine resistance and/or estrogen receptor-positive tumors.
In addition, FGFR4 expression is also related to breast cancer progression, breast cancer cell line survival, and resistance to chemotherapy
.

Figure 3.
2 The overexpression status of FGFR4 and FGF19 in different tumors

(Image source: Pharmacology & Therapeutics 2020)

4.
FGFR4 inhibitors under research worldwide

From the mode of action, there are two strategies for targeting FGFR4: the covalent binding of cysteine, and the use of relatively small cysteine ​​residues to create a subpocket to achieve selectivity
.

Further, from the perspective of clinical trial speed, the fastest-growing varieties mainly include Roblitinib of Novartis in clinical phase II, Fisogatinib of Blueprint Medicines, H3B-6527 of foreign company H3Biomedicine in clinical phase I, INCB-62079 of Incyte and domestic The pharmaceutical company Nuocheng Jianhua’s ICP-105, Guangdong Zhongsheng’s ZSP-1241, Zhejiang Hisun’s HS-236, Betta Pharmaceutical’s BPI-43487, and Beijing First Pharmaceutical Holdings’ SY-4798 are briefly introduced as follows
.

➢ Roblitinib

The development company is Novartis, which is a reversible covalent FGFR4 inhibitor, which is obtained through high-throughput screening and structural modification and reconfiguration.
It is mainly used to treat HCC expressed by FGFR4 and β-klotho
.
An international phase I/II trial was launched in HCC patients in December 2014, a clinical trial application was submitted in China in December 2015, and a phase Ib/II trial for advanced solid tumors and HCC was launched in August 2020
.
PS: Genting Xinyao has domestic development rights
.

➢ Fisogatinib

The development company is Blueprint Medicines, which is a highly selective irreversible covalent FGFR4 inhibitor.
The compound is restructured through layers of BGJ398 and BLU9931; Phase I clinical trials for hepatocellular carcinoma started in 2015, with data showing 77 patients Among them, 16% had objective remission, 68% had disease control, and 49% had tumor burden reduction
.
In December 2019, a phase Ib/II trial in combination with the anti-PD-L1 monoclonal antibody sugemalimab for locally advanced or metastatic HCC was launched in China; in 2020, the design decision of CStone Pharmaceuticals has greatly accelerated clinical progress
.
PS: CStone Pharmaceuticals has domestic development rights
.

➢ H3B-6527

The development company is H3Biomedicine (a subsidiary of Eisai), which is also modified based on the structure of BGJ398.
The goal is to covalently bind to the cysteine ​​of FGFR4 kinase.
It is a selective covalent and irreversible FGFR4 inhibitor; The clinical trials mainly point to advanced hepatocellular carcinoma
.
In July 2016, the phase I trial of HCC started, and in September 2017, the FDA granted the title of orphan drug for the treatment of HCC
.

➢ INCB-62079

The development company is Incyte, a selective and irreversible inhibitor of FGFR4.
In May 2017, a phase I trial was launched in patients with hepatocellular carcinoma and other solid tumors.
The trial will recruit about 100 HCC, FGF19/FGFR4 altered HCCs, Patients with cholangiocarcinoma, esophageal cancer, nasopharyngeal cancer, and severe ovarian cancer; in August 2019, the drug was listed as a development specifically for liver cancer
.

➢ ICP-105

The development company is Nuocheng Jianhua, an orally effective and selective FGFR4 inhibitor, which is mainly clinically directed to hepatocellular carcinoma with excessive activation of the FGFR4 pathway; in September 2018, the phase I trial of advanced solid tumors was initiated
.

➢ ZSP-1241

The development company is Guangdong Zhongsheng Pharmaceutical and WuXi AppTec.
It is a selective inhibitor of FGFR4, as a tablet preparation, clinically used to treat liver cancer, gastric cancer, bile duct cancer, esophageal cancer, colorectal cancer and other advanced solid tumors
.
In November 2018, China initiated a phase I study for the treatment of advanced solid tumors
.

➢ HS-236

The development company is Zhejiang Hisun Pharmaceutical, a selective FGFR4 inhibitor, used as an oral capsule preparation for the treatment of advanced solid tumors, mainly hepatocellular carcinoma; Phase I trials for advanced solid tumors have been launched in December 2020
.

➢ BPI-43487

The development company is Betta, an oral FGFR4 inhibitor for the treatment of FGF19-positive solid tumors, including hepatocellular carcinoma and cholangiocarcinoma; in March 2021, it has been included in the company's official website for the phase I clinical development of advanced solid tumors
.

➢ SY-4798

The development company is the first drug holding company, an FGFR4 inhibitor, oral tablet, for the treatment of FGF19-positive advanced solid tumors; in April 2021, China launched a phase I trial for advanced solid tumors
.

(Note: The above companies are in no particular order)

references:

1.
Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver.
Journal of Hepatology 2021.
doi.
org/10.
1016/j.
jhep.
2021.
07.
029.

2.
FGFR4: A promising therapeutic target for breast cancer and other solid tumors.
Pharmacology & Therapeutics 2020.
doi.
org/10.
1016/j.
pharmthera.
2020.
107590.

3.
Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors.
European Journal of Medicinal Chemistry 2021.
doi.
org/10.
1016/j.
ejmech.
2021.
113794.

4.
FGFR4: A promising target for the treatment of liver cancer.
CNKI

5.
The role of FGF19-FGFR4 signaling pathway in the progression of liver cancer and the development of related drugs.
CNKI

6.
http:// Official websites and annual reports of major companies