Two Hot Targets: FGFR4 and HPK1

Fibroblast growth factor receptor (FGFR) is a highly conserved receptor tyrosine kinase (RTK) involved in cell growth, differentiation, survival, migration and angiogenesis. FGFR4 is a member of the FGFR family. A protein that assumes the role of an immune checkpoint also exists within the cell, a protein named hematopoietic progenitor kinase 1 (HPK1).

Here Creative Biolabs will introduce these two targets, FGFR4 and HPK1, exploring whether they are worth investigating and how they will address the therapeutic needs of patients.

A Breakthrough in Hepatocellular Carcinoma Therapeutic Need: FGFR4

FGFR is involved in cell growth, differentiation, survival, migration and angiogenesis. The FGFR family consists of four submembers, FGFR1, FGFR2, FGFR3 and FGFR4. These members have different binding affinities to different FGF ligands and thus have their own division of labor.

FGFR is one of the links in maintaining physiological homeostasis in the human body, which also means that once FGFR-mediated signaling is dysregulated, some physiological functions become imbalanced, which in turn leads to the development of diseases. Some studies have shown that FGFR or ligands are abnormally expressed or mutated or fused in a variety of malignant tumors such as hepatocellular carcinoma, uroepithelial carcinoma, and biliary tract cancer.

  • FGFR1 overexpression is common in breast cancer, non-small cell lung cancer and head and neck cancer.
  • FGFR2 overexpression is more common in breast cancer, intrahepatic cholangiocarcinoma and endometrial cancer.
  • FGFR3 is significantly overexpressed in uroepithelial carcinoma.
  • The ligand of FGFR4 is overexpressed in hepatocellular carcinoma.

As a result, FGFR inhibitors have emerged. However, the lack of selectivity can lead to off-target toxicity.

FGFR4, with its unique protein structure and relatively specialized ligands, and its clear causal relationship with the development of primary hepatocellular carcinoma, is an ideal target for innovative drugs.

An Alternative Route to Immune Checkpoint Inhibition: HPK1

HPK1 was discovered in 1996, but was recognized as an immune checkpoint only in 2007, and its structure was confirmed 12 years later. HPK1 has been found to be overexpressed in a variety of malignant tumors including uroepithelial, pancreatic, and colon cancers, and it can synergize with PD-1/PD-L1 to produce anti-tumor effects.

This feature implies that HPK1 has the potential for application comparable to PD-1/PD-L1 and is expected to solve the problem of drug resistance to PD-1/PD-L1 drugs, as well as bring a brand-new therapeutic option for patients with cancer types unsuitable for treatment with PD-1/PD-L1 drugs.

However, few relevant targeted drugs have emerged for HPK1. This is due to the fact that a slight design error can affect the selectivity of the molecule and lead to off-target effects. The specific reasons for this are as follows.

HPK1 is actually a member of the mitogen-activated protein kinase (MAP4K) family, and the other five members are germinal center kinase (GCK), GCK-like kinase (GLK), HPK1/GCK-like kinase (HGK), SPS1/STE20 homologous kinase (KHS), and monstrous-like/Nck-related kinase (MINK). The proteins of HPK1 and the other five MAP4K family members are structurally very similar but functionally distinct, and the functions of some members have not been well studied to date.

Now these two targets FGFR4 and HPK1 have the hope of bringing therapeutically meaningful drugs to more patients. Creative Biolabs will work together with all parties to continue to efficiently promote the research of FGFR4 and HPK1 targets. We are at the forefront of these advances, and are confident in offering customer-satisfied immune checkpoint targeted small molecule development services to global clients. If you have an interest in immune checkpoint research, please do not hesitate to contact us with your particular needs.

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