Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer
Selective inhibition of ADAM metalloproteases as a novel approach for modulating ErbB pathways in cancer
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DOI：
10.1158/1078-0432.ccr-06-2116
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发表时间：
2007-03-15
影响因子：
11.5
通讯作者：
Vaddi, Kris
中科院分区：
文献类型：
--
作者：
Fridman, Jordan S.;Caulder, Eian;Vaddi, Kris
目的：ErbB受体信号通路是细胞命运的重要调节因子，其通过（表观）遗传改变的失调在多种癌症中起病因学作用。ErbB配体被合成为膜结合的前体，其被锌依赖性金属蛋白酶的ADAM家族的成员切割。这个过程，称为胞外域脱落，是必不可少的ErbB配体的功能激活。最近的研究表明，ErbB配体水平升高可能会规避ErbB靶向治疗的有效性。在这里，我们描述了发现和临床前开发的有效的，选择性抑制剂的ErbB配体shedding.Experimental Designing：一系列的生化和细胞为基础的测定，以确定ErbB配体脱落的选择性抑制剂。这些化合物的治疗潜力进行了评估，在多个体内模型的癌症和基质金属蛋白酶相关toxicity.Results：INCB 3619被确定为一个代表性的选择性，强效，口服生物可利用的小分子抑制剂的一个子集的ADAM蛋白酶，阻止脱落的ErbB配体。向荷瘤小鼠施用INCB 3619减少了体内ErbB配体脱落并抑制了ErbB途径信号传导（例如，Akt的磷酸化）、肿瘤细胞增殖和存活。此外，INCB 3619协同与临床相关的癌症治疗，并没有表现出明显的或复合毒性，包括纤维增生，剂量限制性毒性与广谱基质金属蛋白酶inhibitors.Conclusions：抑制ErbB配体脱落提供了一种潜在的新的和耐受性良好的治疗策略，用于治疗人类癌症，目前正在临床上进行评估。
Purpose: ErbB receptor signaling pathways are important regulators of cell fate, and their dysregulation, through (epi)genetic alterations, plays an etiologic role in multiple cancers. ErbB ligands are synthesized as membrane-bound precursors that are cleaved by members of the ADAM family of zinc-dependent metalloproteases. This processing, termed ectodomain shedding, is essential for the functional activation of ErbB ligands. Recent studies suggest that elevated levels of ErbB ligands may circumvent the effectiveness of ErbB-targeted therapeutics. Here, we describe the discovery and preclinical development of potent, selective inhibitors of ErbB ligand shedding.Experimental Design: A series of biochemical and cell-based assays were established to identify selective inhibitors of ErbB ligand shedding. The therapeutic potential of these compounds was assessed in multiple in vivo models of cancer and matrix metalloprotease related toxicity.Results: INCB3619 was identified as a representative selective, potent, orally bioavailable small-molecule inhibitor of a subset of ADAM proteases that block shedding of ErbB ligands. Administration of INCB3619 to tumor-bearing mice reduced ErbB ligand shedding in vivo and inhibited ErbB pathway signaling (e.g., phosphorylation of Akt), tumor cell proliferation, and survival. Further, INCB3619 synergized with clinically relevant cancer therapeutics and showed no overt or compounding toxicities, including fibroplasia, the dose-limiting toxicity associated with broad-spectrum matrix metalloprotease inhibitors.Conclusions: Inhibition of ErbB ligand shedding offers a potentially novel and well-tolerated therapeutic strategy for the treatment of human cancers and is currently being evaluated in the clinic.