In 2001, the first kinase inhibitor imatinib was approved by the FDA and successfully marketed, representing an important breakthrough of kinase drugs in the field of molecular targeted cancer treatment. Recently, an article entitled "Trends in Kinase Drug Discovery: Targets, Applications and Inhibitor Design" (IF: 84.69) published in Nature sub-journal Nature Reviews Drug Discovery reviewed the development history of kinase drugs in the past 20 years and analyzed the prospect and development trend of kinase drugs in tumor treatment. So, what is a kinase? What are the types of kinases? Why are they considered "promising" in the anti-tumor field?
Kinase is a enzyme that catalyze the action of a high-energy donor (such as ATP) to transfer a phosphate group to a particular target molecule (substrate) and the process is called phosphorylation. At present, common kinase products can be roughly divided into the following four categories: protein kinase, fat kinase, fructose kinase and mutant kinase, of which, protein kinase is the most common and the largest kinase family in the system. Protein kinases (PK) are enzymes that modify the protein function by attaching phosphate groups to other proteins. They are key controllers of multiple signal transduction pathways and important participants in most life processes in cells, so they have long been regarded as targets for cancer treatment interventions in terms of health and disease.
Protein phosphorylation is the most basic, common and important mechanism for regulating and controlling the activity and function of the protein. Protein phosphorylation refers to the process catalyzed by protein kinase to transfer a phosphate group on ATP to a substrate protein amino acid residue (serine, threonine, or tyrosine) with a free hydroxyl (-OH) group. The products are phosphoprotein and ADP. Most kinases act on serine or threonine, while some act exclusively on tyrosine. These two types of acid-phosphorylated enzymes have different functions and, however, there are some bifunctional enzymes that can act on all three at the same time, such as MEK (mitogen-activated proteinkinase kinase, MAPKK). Among them, tyrosine phosphorylation process not only can deform and activate the activity of proteins, its more important function is binding protein. A structural gene is provided to facilitate its interaction with other protein to form a multiprotein complex. The protein complex is formed to further promote protein phosphorylation. Over and over again, the signal produced by the initial phosphorylation of protein goes on like step by step.
Therefore, tyrosine phosphorylation and the formation of polyprotein complexes constitute the basic mechanism of cell signal transduction, and the enzyme that catalyzes protein tyrosine phosphorylation--tyrosine kinase has become a key molecule for signal transduction mechanism and control of cell growth. Tyrosine kinase and protein tyrosine phosphorylation also play a decisive role in tumor development and growth. Many antitumor drugs have been developed based on these molecules.
Over 500 protein kinases have been found so far, and the tree diagram in Figure 1 depicts the relationships among the complete superfamily members of human protein kinases. They were classified into five classes based on their phosphorylated substrate amino acid residues: tyrosine (Tyr) protein kinase, serine/threonine (Ser/Thr) protein kinase, histidine protein kinase, tryptophan protein kinase, and aspartyl/glutamyl protein kinase. Among them, tyrosine protein kinase plays an important role in the regulation of intracellular signaling pathways and has been widely studied.
Protein tyrosine kinase(PTK) is a type of kinase that can catalyze the transfer of γ-phosphate from ATP to protein tyrosine residues. The common feature is that its carboxy terminal has a typical PTK domain. PTK can catalyze its own or substrate phosphorylation, and plays an important role in cell growth, proliferation, and differentiation. Most of the tyrosine protein kinases discovered so far are oncogene products of oncogenic RNA viruses and can also be produced by proto-oncogenes in vertebrates.
Tyrosine protein kinases can be divided into receptor and non-receptor types. Common receptor-type tyrosine protein kinases (RTK) include epidermal growth factor receptor (EGFR) family, insulin receptor family, platelet-derived growth factor receptor (PDGFR) family, and fibroblast growth factor receptor (FGFR) family. Abnormal activation of receptor-type tyrosine protein kinase is closely related to angiogenesis, tumor invasion and metastasis.
Table 1 Classification and indications of receptor tyrosine protein kinase
Receptor family | Receptor | Indication |
---|---|---|
Epidermal growth factor receptor (EGFR) | HER1、HER2、HER3、HER4 | Non-small cell lung cancer, head and neck tumors, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, head and neck tumors |
Insulin receptor (InsR) | IGF-I、IGF-Ⅱ、INSR、INSRR | Breast cancer, neck cancer, colon cancer, lung cancer, blood tumor |
Platelet-derived growth factor receptor (PDGFR) | PDGFRα、PDGFRβ、CSF-1R、SCFR、FLK2、FLT3 | Hypereosinophilic syndrome, mastocytosis, gastrointestinal stromal tumor, epithelial cell tumor, leukemia |
Fibroblast growth factor receptor (FGFR) | FGFR1、FGFR2、FGFR3、FGFR4 | angiogenesis |
Vascular endothelial growth factor receptor (VEGFR) |
VEGFR1、VEGFR2、VEGFR3、VEGFR4 |
Lung cancer, liver cancer, ovarian cancer, |
Hepatocyte growth factor receptor (HGFR) | HGFR、MSPR | Breast cancer, colon cancer, stomach cancer, prostate cancer, kidney cancer |
Tie family angiopoietin receptors | Tie1 、TEK | Capillary hemangioblastoma, vascular endothelial cell tumor, gastric adenocarcinoma cell, hepatocellular carcinoma |
There are ten main families of non-receptor tyrosine kinases, of which four families are clearly closely related to the occurrence of malignant tumors: ABL family, JAK family, SRC family and FAK family.
Table 2 Classification and indications of non-receptor tyrosine protein kinases
Receptor family | Receptor | Indication |
---|---|---|
ABL family | ABL1、ARG | Chronic myeloid leukemia |
ACK family | ACK1、TNK1 | Prostate cancer, lung cancer, breast cancer |
CSK family | CSK、MATK | lymphoma |
FAK family | FAK、PYK2 | Breast cancer and liver cancer |
FES family | FES、FER | Lung cancer and liver cancer |
FRK family | FRK、BRK、SRMS | Glioma, non-small cell lung cancer |
JAK family | JAK1、JAK2、JAK3、TYK2 | Leukemia, lymphoma, myelofibrosis |
SRC-A family | SRC、FGR、FYN、YES1 | Glioma, pancreatic cancer, prostate cancer |
SRC-B family | BLK、HCK、LYN | Breast cancer, lung adenocarcinoma, non-small cell lung cancer |
TEC family | TEC、BMX、BTK、ITK、TXK | Prostate, breast and renal cell carcinoma |
SYK family | SYK、ZAP70 | Chronic lymphocytic leukemia, small lymphocytic lymphoma |
Drugs targeting tyrosine kinases are divided into antibodies and small molecule inhibitors. At present, 87 small molecule kinase inhibitors have been approved worldwide. Among the 71 small molecule kinase inhibitors approved by FDA, most are tyrosine protein kinase inhibitors (Table 3). Oncology is the most important application field. In addition, according to the information from clinical trials of SMKIs, about 110 novel kinases are currently being studied as targets, and about 45 targets of approved kinase inhibitors only account for about 30% of human kinase groups, indicating that there are still a large number of undeveloped fields awaiting exploration for this kind of drug [2].
Table 3 FDA-approved tyrosine protein kinase inhibitors
Targeted kinase | Drug Name |
---|---|
ALK | Alectinib, Crizotinib, Brigatinib, Lorlatinib, Ceritinib |
Bcr-Abl | Bosutinib, Dasatinib, Nilotinib, Ponatinib, Imatinib |
BTK | Acalabrutinib, Ibrutinib, Zarubrutinib |
C-Met | Crizotinib, Cabozantinib |
EGFR | Erlotinib, Afatinib, Gefitinib, Dacomitinib, Osimertinib Neratinib |
JAKs | Ruxolitinib, Baricitinib, Tofacitinib |
PDGFR | Lenvatinib, Nintedanib, Ponatinib, Regorafenib, Imatinib |
RET | Lenvatinib, Regorafenib, Sunitinib, Vandetanib |
SRC | Dasatinib, Bosutinib, Ponatinib |
VEGFR | Axitinib, Lenvatinib, Regorafenib, Pazopanib, Nintedanib, Sorafenib, Sunitinib |
FGFR | Nintedanib, Erdafitinib |
c-Kit | Pexidartinib, Avapritinib |
FLT3 | Gelteritinib, Sunitinib |
References
[1] Manning G, Whyte D B, Martinez R, et al. The Protein Kinase Complement of the Human Genome[J]. Science, 2002, 298(5600).
[2] Attwood M M, Fabbro D, Sokolov A V, et al. Trends in kinase drug discovery: targets, indications and inhibitor design[J]. Nature reviews drug discovery, 2021, 20(11).
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