Kinase drugs: the cornerstone in the future

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Kinase can add phosphate group (PO4^3-) to target protein, lipid and nucleic acid molecules. There are at least 500 genes encoding kinases in the human genome. Among them, protein kinase can phosphorylate serine, threonine, tyrosine and other amino acids by adding phosphate groups to protein. Kinase makes lipid molecules phosphorylated, such as phosphoinositide formed by phosphorylation of inositol, which can act as a second messenger to participate in intracellular signal transduction. Kinases add phosphate to nucleosides to form nucleotide monophosphate, which play a role in DNA synthesis. In the tricarboxylic acid cycle, a group of kinase involved in the phosphorylation step is also crucial in ATP production (1).

American biochemists Krebs and Fisher jointly won the 1992 Nobel Prize in physiology or medicine for discovering the phosphorylation process of proteins. In the process of studying glycogen production, they explained that protein kinase could transfer the phosphate group of ATP to amino acids. This reversible biochemical process formed by the phosphorylation of phosphatase and kinase constituted the biochemical basis of the basic activities of cells, and participated in the pathophysiological processes such as tumors, cardiovascular diseases and diabetes. It also opened up researchers' exploration of kinases for more than 20 years. Krebs was born in Lanxin, Iowa, on June 6, 1918, and died in Seattle, Washington, on December 21, 2009. Fisher was born in Shanghai, China on April 6, 1920, and received a doctorate in chemistry from Geneva University in 1947. After 1953, he was teaching at Washington University with Krebs (2,3).

Starting from the first kinase inhibitor Imatinib, in the past 20 years, the research and development of kinase drugs has achieved a transformation from epistemology to clinical value, and has formed a unique field, a thinking model that everyone can't get around when thinking about cell behavior, and an intelligent command system that flickers like a traffic light in an urban traffic network, running in an orderly way, until the end of cell life. It is difficult to say whether this theoretical model has limited people's imagination of intracellular space and molecular flexibility, but the strong evidence of clinical research has irresistibly pushed these drugs to the clinic and saved countless patients. At that time, the dilemma of drug shortage was deeply and vividly depicted in a film called "I'm not the God of medicine".

The great success of kinase drugs makes everyone believe that this kind of drugs will still develop unstoppably in the next ten or twenty years (4), the iterative speed may be much faster than that of mobile phones. Unfortunately, this kind of iteration may not come from active exploration, but rather from passive response to acquired resistance of tumor cells to various kinase inhibitors. The development of immunooncology may expand the field of vision for the study of kinase drugs in the theoretical model. Tumor cells, as individuals, have their unique biological behavior, but they live in the surrounding environment after all. Like the basic theory of evolution, the complexity and dynamic remodeling of the microenvironment constitute a more chaotic picture, which makes such biological structure more nonlinear. The phosphorylation and dephosphorylation of kinases need biochemical description, the catalysis of kinases and the structural and biological deconstruction of active centers. Gene editing and single-cell omics also provide powerful tools for the macro understanding of kinase omics. However, in the face of such a complex and dynamic nonlinear system, integrated research is needed, which requires the development of mathematical theory and tools as well.

References:

1, Cooper JA. Kinase. Britannica Academic, Encyclopædia Britannica. 2018. Jul 24.

2, Edwin Gerhard Krebs. Britannica Academic, Encyclopædia Britannica. 2010. Feb 11.

3, Edmond H. Fischer. Britannica Academic, Encyclopædia Britannica. 2016. Apr 27.

4, Cohen P, Cross D, and Janne PA. Nat Rev Drug Discov. 2021; May 17:1-19.