T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs

Abstract

The invention provides a T790M mutant EGFR inhibitor and an application of the same in preparation of antitumor drugs. The inhibitor is a pyrimidine compound with structural characteristics of a formula (I). The compound can inhibit various tumor cells and particularly can act on EGFR L858R / T790M and EGFR E 745_A750 / T790M lung cancer cells selectively, and the IC 50 of the compound is 10 timers and even 100 times higher than that of wild cancer cells. The compound is the protease inhibitor which is capable of overcoming prior EGFR-TKI drug resistance and has selectivity and can be applied to preparation of antitumor drugs. (img file= 'DDAS0000708455660000011. TIF' wi= '716' he= '576' / ).

Description

technical field [0001] The invention relates to a drug for treating tumors, in particular to an inhibitor of T790M mutant EGFR and its application in the preparation of anti-tumor drugs. Background technique [0002] In the past 30 years, the mortality rate of lung cancer has increased by 465%, and the incidence rate has increased by 26.9% every year. It has replaced liver cancer as the first cause of death from malignant tumors in my country. This disease with the highest mortality rate is a serious threat to human health. Among them, non-small cell lung cancer (NSCLC for short) accounts for more than 80% of all lung cancers, only one-third of NSCLC patients have the opportunity for surgical treatment, and about 70% of the patients are localized at the time of treatment. Late stage or distant metastasis, lost the chance of surgical treatment. In this case, drug treatment is particularly important. [0003] In the traditional cancer treatment process, chemotherapy is the ...

AI Technical Summary

Problems solved by technology

Further studies have confirmed that due to the T790M mutation of the EGFR gene, that is, the encoded threonine is converted to methionine, resulting in steric hindrance that hinders the combination of the inhibitor with the ATP binding region and ultimately leads to the loss of inhibitor activity.

At present, studies have also shown that the mutation of the T790M site does not directly affect the affinity of the inhibitor to EGFR, but the mutation leads to a great increase in the affinity of EGFR and ATP, which greatly reduces the affinity of the inhibitor to EGFR ( Inhibitors compete with ATP for binding)

The second-generation inhibitors, such as afatinib and dacomitinib, are superior to the first-generation in that they have increased recognition of EGFR, which can distinguish tumor cells from normal cells, so that side effects will be reduced; but These molecules have poor selectivity to the EGFRT790M mutant, resulting in a low clinically tolerated dose of the drug. At its maximum tolerated dose (MTD), the drug cannot reach its effective concentration in the body, making it ineffective for most drug-resistant patients

[0005] In short, the current EGFR tyrosine kinase inhibitors (EGFR-TKI) still cannot solve the clinical pressure caused by drug resistance, and most of the existing drugs are based on quinazoline or quinoline amines EGFR reversible or irreversible inhibitors, the toxicity and side effects caused by poor selectivity to wild-type cells are also inevitable

Therefore, there is an urgent need for new types, especially compounds with novel frameworks, to solve problems such as drug resistance and poor selectivity.

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