How The F,Cl Atoms In Benzene Ring Of 5-Methylpyrimidine-pyridine Derivatives Affect The Inhibition Ability Of EGFR^{L858R/T790m/C797S}

As everyone knows,abnormal cell proliferation and abnormal metastasis will greatly enhance the incidence of cancer.All kinds of cancers have high incidence rate and high mortality rate.So all kinds of cancer are malignant diseases that will threaten human health and even lead to death.From the perspective of biochemical theory,when some protein kinases are overexpressed or abnormally expressed in cancer cells,resulting in abnormal signal transduction,they will interfere with the proliferation,differentiation,metabolism,apoptosis and other physiological processes of normal cells in varying degrees.Cancer is a kind of disease characterized by abnormal cell proliferation and metastasis.It has the characteristics of high morbidity and mortality.It is one of the malignant diseases that threaten human health and lead to death.When some protein kinases over expression or abnormal expression in cancer cells leads to abnormal signal transduction,which is involved in many physiological processes such as cell proliferation,differentiation,metabolism,apoptosis,etc.The pathogenesis of non-small cell lung cancer（NSCLC）is closely related to the mutant kinase activity in epidermal growth factor receptor（EGFR）,abnormal signal transduction is closely related to the occurrence of cancer,it can accelerate cellular apoptosis,antagonize angiogenesis,and inhibit tumor metastasis and tumor growth.Therefore,it has become one of the most important research fields to design and develop kinase inhibitors that act on oncogenic EGFR.Lung cancer is the most frequent cause of cancer-related deaths worldwide,and mutations in the kinase domain of the epidermal growth factor receptor（EGFR）are a common cause of non-small-cell lung cancers,a major subtype of lung cancers.Recently,a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants.However,the binding-based inhibition mechanism has not yet been determined.In this study,we carried out molecular dynamic simulations and free energy calculations for EGFR derivatives to fill this gap.Based on the investigation,the three factors that influence the inhibitory effect of inhibitors are as follows:（1）The substitution site of the Cl-atom is the main factor influencing the activity through steric effect;（2）The secondary factors are repulsion between the F-atom（present in the inhibitor）and Glu762,and the blocking effect of Lys745 on the phenyl ring of the inhibitor.（3）The two factors function synergistically to influence the inhibitory capacity of the inhibitor.The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.This paper summarizes the latest development on the discovery of a fourth-generation EGFR-TKI,called“8r-B”which is noncovalent reversible epidermal growth factor receptor inhibitors.Cell proliferation assays showed that8r-B effectively and selectively inhibited the growth of EGFR^L858R/T790M/C797S858R/T790M/C797S and EGFR^{del745-750/T790M/C797S}dependent cells.This compound occupied the ATP binding site of the EGFR kinase,may serve as a basis for the development of fourth-generation EGFR inhibitors for oncogenic mutants.