What Is a Tyrosine Kinase Inhibitor?

Tyrosine kinase inhibitors (English abbreviations TKI ) are a class of compounds that inhibit the activity of tyrosine kinases.

Tyrosine kinase inhibitors (English abbreviations TKI ) are a class of compounds that inhibit the activity of tyrosine kinases.

Tyrosine kinase inhibitors can be used as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, and can also be used as tyrosine analogs to block tyrosine kinase activity and inhibit cell proliferation. An antitumor drug.

Chinese name

Tyrosine kinase inhibitor

Foreign name

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (English abbreviation Tyrosine kinase inhibitors TKI ) are a class of compounds that can inhibit the activity of tyrosine kinases.

Tyrosinekinase (tyrosinekinase) is a type of kinase that catalyzes the transfer of -phosphate from ATP to protein tyrosine residues. It can catalyze the phosphorylation of protein tyrosine residues on a variety of substrates and promote cell growth, proliferation, and differentiation. Plays an important role. Most of the protein tyrosine kinases discovered to date are oncogene products belonging to oncoRNA viruses, and can also be produced by proto-oncogenes in vertebrates.

Tyrosine kinase inhibitors can be used as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, and can also be used as tyrosine analogs to block the activity of tyrosine kinases and inhibit cell proliferation. An antitumor drug.

Tyrosine kinase inhibitor 2. Mechanism of action

Tyrosine kinase inhibitors inhibit tumor cell growth and proliferation, and promote apoptosis by inhibiting cell signal transduction. ^[1]

For example, the currently most commonly used small molecule TKIs for tyrosine kinases against BCR-ABL fusion genes in clinical practice include the first-generation drug imatinib, and the second-generation drug dasatinib (Stardace ) And nilotinib. Tyrosine kinase inhibitors play an anti-leukemia effect mainly by inhibiting the BCR-ABL fusion protein.

Tyrosine kinase inhibitors III. Advantages of tyrosine kinase inhibitors

Tyrosine kinase inhibitors are highly selective and have few side effects ^[1] . The drugs on the market have shown their superiority in the treatment of various diseases such as chronic myelogenous leukemia, non-small cell lung cancer, and renal cell carcinoma, which are called traditional therapeutic drugs, and some of them have become first-line drugs for treating tumors.

Dasatinib, the second-generation tyrosine kinase inhibitor, has been approved for chronic myeloid leukemia ( CML ) and Philadelphia chromosome-positive ( Ph + ) acute lymphoblastic leukemia in 42 countries around the world since it was approved by the FDA in 2006. ( ALL ) treatment (first-line and second-line treatment). On September 7, 2011, the State Food and Drug Administration ( CFDA ) approved Starda for second-line treatment of chronic myelogenous leukemia at various stages.

Tyrosine kinase inhibitors

Most signal transduction inhibitors only inhibit tumor growth and cannot completely kill tumor cells. Therefore, from the current research situation, such inhibitors should be combined with conventional chemotherapy and radiation therapy to achieve better efficacy. Cells contain complex signal transduction pathways. Even if some signaling pathways of tumor cells are inhibited, other pathways can still transduce signals and may produce compensatory up-regulation, which affects the therapeutic effect. Therefore, the resistance to signal transduction The tumor strategy should also be combined with multiple pathways and multiple targets, which may achieve better results. From the perspective of long-term medication, combined therapy can also reduce drug resistance. ^[2]

Tyrosine kinase inhibitors

Inhibitors have become a hot field in the world's anti-tumor research. Major international research institutions and pharmaceutical groups attach great importance to drug development targeting tyrosine kinases, including the development of small molecule tyrosine kinase inhibitors, tyrosine Kinase-specific monoclonal antibodies and antisense oligonucleotides. At present, many inhibitors and antibodies have entered the phase - clinical trial stage, and some have been marketed.

Multi-target drugs can inhibit multiple signal pathways or multiple molecules in one signal pathway. A large number of clinical studies have confirmed that this class of drugs is effective for tumors resistant to single-target inhibitors. In recent years, the United States has approved the listing of multiple low-molecular multi-target tyrosine kinase inhibitors, including imatinib, sorafenib, sunitinib, lapatinib, and dasatinib. It has been reported that resistance to mutations in BCR-ABL and platelet-derived growth factor receptor kinase domains have been observed in cancer cells of patients receiving imatinib. The extended sunitinib study included 4,000 patients in 36 countries. A subgroup analysis of safety showed that the adverse reactions related to treatment in this group were mainly diarrhea, fatigue, nausea, etc., which were basically tolerable.

With the development of modern molecular biology technology and a clear understanding of the structure of tyrosine kinases, so-called gene therapy drugs have emerged. The main methods of gene therapy are: gene replacement or supplementation of antisense oligonucleotides to down-regulate oncogene expression, RNA interference (post-transcription level gene silencing); cytokine gene introduction effector cell drug-sensitive gene therapy and multidrug resistance gene therapy Cancer genetic engineering vaccines and more. ^[2]

Tyrosine kinase inhibitors

Taking tyrosine kinase inhibitors as an example, the research and development of anti-tumor drugs from cell signal transduction pathways is a hot spot in the future, and it is full of hardships, opportunities and challenges. With the deepening of people's understanding of the mechanism of cell signal transduction, it provides a theoretical basis for the rational design of drugs that inhibit signal transduction, and also helps clear the direction for humans to defeat tumors.