靶向耐药肺癌的高选择性共价Bmx抑制剂的设计、合成及其生物活性研究

Multidrug resistance of good targets for lung cancer, such as epidermal growth factor receptor (EGFR), is one of the major causes of failure in its clinical treatment. Bone marrow tyrosine kinase gene in chromosome X (Bmx) is widely expressed in lung that is a key transporter in the downstream signaling pathways of EGFR. The transmission of various signals for EGFR will be severely obstructed once Bmx is inactivated, leading to slow down tumor progression of lung cancer and resistant lung cancer. More importantly, homozygous Bmx knockout mice have a normal lifespan without any obviously altered phenotype, suggesting that therapies based on Bmx inhibition might have relatively few side effects. Totally speaking, Bmx is a novel, safe and extremely potential therapeutic target for lung cancer and resistant lung cancer. In our previous study, a covalent Bmx inhibitor B6 (IC50 = 35.7 nM) has been designed and synthesized using its classic Cys496 near the ATP binding domain to form a covalent interaction with Bmx, which can effectively treat non-small cell lung cancer with drug resistance both in vitro and in vivo. Given that the kinase selectivity and bioactivity of B6 are not so high, this project will take it as a lead compound, design and synthesize several series of novel Bmx inhibitors through the technology of computer-aided drug design, establish an instructive structure-activity relationship. In an attempt to obtain selective covalent Bmx inhibitors with high potential and low toxicity which can be orally administrated for the treatment of resistant lung cancer, candidate compounds will be selected to evaluate their therapeutic effects for drug-resistant lung cancer in vitro and in vivo, as well as explore their molecular mechanisms.

肺癌标志物如表皮生长因子受体（EGFR）的多药耐药性是导致其临床治疗失败的最主要原因之一。骨髓X连锁酪氨酸激酶（Bmx），在肺部广泛表达，是EGFR下游信号通路的关键传递分子，当其沉默后，各类EGFR信号传送将严重受阻，延缓肺癌和耐药肺癌疾病进展；且Bmx纯合子小鼠经基因敲除后表型正常，说明Bmx是安全的治疗肺癌和耐药肺癌的新型潜力靶点。在前期研究中，我们利用Bmx在ATP结合域附近典型的Cys496残基设计合成了共价抑制剂B6（IC50=35.7nM），并在体内外实验中证实其能有效治疗耐药非小细胞肺癌，但存在选择性和活性不高等问题。本项目拟以B6为先导化合物，结合计算机辅助药物设计技术，设计并合成多类结构新颖的Bmx抑制剂，建立具有指导意义的构-效关系；并通过体内外实验综合评价化合物对耐药肺癌的治疗效果，探讨其作用机制，力争获得高效低毒的、可用于口服治疗耐药肺癌的选择性共价Bmx抑制剂。

骨髓X连锁酪氨酸激酶（Bmx），广泛表达于骨髓、单核细胞、上皮和内皮细胞、肺部和心脏等组织，通过介导Akt/mTOR、MAPKs 和NF-κB 等信号通路，参与多种癌症进展和免疫调节；重要的是，Bmx基因敲除小鼠表型正常，因此，Bmx是多种疾病治疗的安全的潜力靶点。本项目以具有Bmx抑制作用的依鲁替尼（IC50=0.8 nM）、B6（IC50=35.7 nM）和T15（IC50=24 nM）为先导化合物，基于它们与Bmx蛋白（PDB：3SXR、3SXS、6I99）的相互作用模式，设计并合成了多个系列化合物，经体外激酶活性筛选，分别获得了Bmx、JAK3&Btk、EGFR（T790M）、JAK3&Bmx共价抑制剂，并建立具有指导意义的构-效关系。其中，JAK3&Btk、EGFR（T790M）共价抑制剂，完善了B6系列衍生物的构效关系，尽管它们分别具有不错的抗B细胞淋巴瘤细胞和肺癌细胞的增殖活性，但结构难以突破已有专利，故停止该类衍生物的研究。Bmx共价抑制剂结构简单新颖，已获得专利授权；部分化合物能同时温和抑制EGFR（T790M），验证本项目所提假设，Bmx共价抑制剂可以失活突变型EGFR；而且，化合物在胃癌（B6a）、耐药肺癌和前列腺癌（B6c）等方面拥有与依鲁替尼相当或优于的治疗效果，其干预机制均在实验中；同时，还发现了Bmx抑制剂（B4a）的免疫抗炎作用。JAK3&Bmx双重共价抑制剂在小鼠心脏器官异体移植（A1-2）和急性炎症足肿胀实验（A1-2和A1-3）中均取得较泛JAK抑制剂托伐替尼更优的治疗效果，再次暗示着Bmx对免疫炎症的调节潜力，目前，该系列化合物就提升Bmx抑制活力在结构优化中，以期获得更加安全高效的免疫调节剂。综上，本项目围绕Bmx靶点展开化合物设计，获得了与Bmx相关的多个系列抑制剂，探索了它们的抗肿瘤及免疫调节作用，为这些领域的药物研究提供选择。

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