Identification and Study of Novel EGFR Kinase Inhibtors

项目总结(见说明)： EGFR激酶抑制剂Gefitinib和Eriotinib治疗突变的非小细胞肺癌(NSCLC)的临床成功受到获得性耐药的最终发展的限制。我们和其他人已经确定了耐药的两种主要机制：获得性EGFR继发性突变(EGFR T790M)和HGF/MET信号的激活(通过MET扩增或通过HGF的自分泌/旁分泌产生)。在这两种情况下，耐药癌症都保持对EGFR信号的依赖，这突显了开发新的EGFR靶向治疗和/或联合治疗方法的必要性。不可逆的基于喹唑啉的EGFR激酶抑制剂，包括HKI-272，PF00299804。和B1BW2992在一些临床前模型中对EGFR T790M有效，但在临床上，由于同时靶向抑制野生型(WT)EGFR，其疗效受到缺乏效力和毒性(皮疹和腹泻)的限制。 最近，我们发现了不可逆的嘧啶类EGFR激酶抑制剂(WZ4002)，它们对突变的EGFR受体具有选择性，并且比现有的不可逆的喹唑啉EGFR抑制剂对EGFR T790M的抑制作用更强。此外，与喹唑啉不可逆的EGFR抑制剂不同，这些药物通过体外模型阻止了EGFR T790M的出现，作为一种耐药机制。虽然这类新的EGFR抑制剂在临床上可能比目前可用的药物更有效，但耐药性仍有望发展到所有不可逆转的EGFR抑制剂。事实上，仅是EGFR共价结合位点(C797S)的突变就足以导致对WZ4002和HKI-272的耐药性。在这个项目中，我们建议开发更多的药物，在C797S和其他耐药突变存在的情况下有效地抑制EGFR。具体目标是1.)表征EGFR小分子激酶抑制剂对不可逆的EGFR激酶抑制剂耐药突变的作用。2.)确定对不可逆的嘧啶类EGFR抑制剂的耐药机制。确定靶向耐药机制对不可逆嘧啶类EGFR抑制剂疗效的影响及耐药性的出现。

PROJECT SUMMARY (See Instructions): The clinical success of EGFR kinase inhibitors gefitinib and eriotinib in EGFR mutant non-small cell lung cancer (NSCLC) is limited by the eventual development of acquired drug resistance. We and others have identified two main mechanisms of drug resistance: acquired secondary mutations in EGFR (EGFR T790M) and activation of HGF/MET signaling (either by MET amplification or by autocrine/paracrine production of HGF). In both instances, the resistant cancers maintain dependence on EGFR signaling, highlighting the need to develop novel EGFR-targeted therapies and/or combination therapeutic approaches. Irreversible quinazoline-based EGFR kinase inhibitors, including HKI-272, PF00299804. and B1BW2992, are effective in some preclinical models against EGFR T790M, but clinically their efficacy has been limited by lack of potency and toxicity (skin rash and diarrhea) due to concurrent on-target inhibition of wild-type (WT) EGFR. Recentiy, we identified irreversible pyrimidine EGFR kinase inhibitors (WZ4002) that are selective for the mutant EGFR receptor and are significantiy more potent against EGFR T790M than existing irreversible quinazoline EGFR inhibitors. Furthermore, these agents, unlike quinazoline irreversible EGFR inhibitors, prevent the emergence of EGFR T790M as a resistance mechanism using in vitro models. Although this new class of EGFR inhibitors may be clinically more effective than currentiy available agents, resistance is nevertheless expected to also develop to all irreversible EGFR inhibitors. In fact, a mutation in the covalent binding site (C797S) of EGFR alone is sufficient to cause resistance to both WZ4002 and HKI-272. In this project we propose to develop additional agents that can effectively inhibit EGFR in the presence of the C797S and other drug resistance mutations. The specific aims are 1.) Characterize EGFR small molecule kinase inhibitors against irreversible EGFR kinase inhibitor resistance mutations. 2.) Identify resistance mechanisms to irreversible pyrimidine EGFR inhibitors and 3.) Determine the impact of targeting drug resistance mechanisms on the efficacy of irreversible pyrimidine EGFR inhibitors and the emergence of drug resistance.