WZ4002，延缓因T790M突变导致易、特、2992的耐药及耐药后的选择

ＨＫＩ-２７２单药效率很差。
联合Mtor药在肺癌上面风险很大啊。

谢谢！楼主，文章十分收益！关于T790M的耐药，我们家的用药过程深有同感，现在有何办法解决这问题？

写的真好，但是好复杂！

老马 发表于 2012-12-7 12:25

                               
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ＨＫＩ-２７２单药效率很差。
联合Mtor药在肺癌上面风险很大啊。

老马~抑制T790HKI272联合Mtor药容易发生感染对吗？我家由于吃2992时间长耐药现在2992联合泰欣生不知道能否克制790耐药 期待奇迹出现！

2992耐药，现在有实例的是用2992联合紫杉醇化疗，群里有个病友稳定8个月了。

seacat 发表于 2012-12-2 13:53

                               
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WZ4002现在开发停滞了，人用的安全剂量都还未有。
耐药的还是上化疗吧。

学习了。感谢海猫从 理论给出可能实践方法

关于WZ4002的研究报告：http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/
（Nature. Author manuscript; available in PMC 2010 June 24.）


Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

Abstract.The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR mutant non-small cell lung cancer (NSCLC) is limited by the development of drug resistance mutations, including the gatekeeper T790M mutation1-3. Strategies aimed at targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild type EGFR4,5. All current EGFR inhibitors possess a structurally related quinazoline based core scaffold and were identified as ATP-competitive inhibitors of wild type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30-100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR, than quinazoline based EGFR inhibitors in vitro and are effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant selective kinase inhibitors.

WZ4002, WZ3146 and WZ8040 are novel EGFR inhibitors, suppress the growth of EGFR T790M containing cell lines and inhibit EGFR phosphorylation

Figure 1

WZ4002 is less potent than quinazoline EGFR inhibitors against wild type EGFR in vitro and in vivo

Figure 2

Crystal Structure of WZ4002 bound to EGFR T790M

Figure 3