WZ4002，延缓因T790M突变导致易、特、2992的耐药及耐药后的选择

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

WZ4002 inhibits EGFR phosphorylation and induces significant tumor regression in murine models of EGFR T790M

Our studies identify a novel structural class of EGFR kinase inhibitors which are effective in vitro and in vivo models harboring the EGFR T790M mutation. Given the dramatic activity in models with established EGFR T790M, we determined whether WZ4002 treatment could also prevent the development of EGFR T790M using in vitro models harboring EGFR activating mutations. Unlike with gefitinib or HKI-272, which when used at their achievable plasma concentrations lead to development of EGFR T790M in vitro13,21,22, we were unable to isolate any EGFR T790M containing clones from WZ4002 treated Ba/F3 or PC9 NSCLC cells (Table S9). These findings suggest that WZ4002 could also be used as initial therapy for EGFR mutant NSCLC patients and may ultimately lead to a longer time to disease progression than currently achieved with gefitinib1.

Figure 4

Mutations, including at the gatekeeper residue, are a common mechanism of drug resistance to kinase inhibitors. The current approach, using a cellular screen expressing the mutant kinase of interest, can be applied to identify novel agents specifically against drug resistance or oncogenic mutations implicated in human cancers. Such agents may truly be cancer selective and clinically more potent and less toxic than those that also concurrently inhibit the wild type kinase. The agents described here are unique in that they inhibit both the drug sensitizing and resistance mutations but are selective against WT EGFR23,24,25. Further studies are needed to determine whether this class of EGFR inhibitors will be clinically effective in patients with EGFR mutant cancers harboring EGFR T790M mediated acquired drug resistance.