PDF(Pubmed)
Abstract：
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
摘要：
免疫调节酰亚胺药物（IMiDs）在多发性骨髓瘤各个阶段的治疗领域中起着至关重要的作用。尽管它们有明显的功效，一些患者可能对IMiD治疗表现出主要耐药性，获得性耐药性通常随着时间的推移而出现，导致不可避免的复发。至关重要的是开发新的治疗选择，以增加治疗库以克服IMiD耐药性。我们设计了,合成，筛选了一类新的多氟化沙利度胺类似物，并研究了它们的抗癌作用，抗血管生成，和使用体外和离体生物学测定的抗炎活性。我们确定了四种显示有效抗骨髓瘤的先导化合物，抗血管生成，使用三维肿瘤球体模型的抗炎特性，体外试管形成，和离体人隐静脉血管生成测定，以及THP-1炎症分析。蛋白质印迹分析研究cereblon下游蛋白（CRBN）的表达，揭示了Gu1215，我们的主要前导候选，通过CRBN独立机制发挥其活性。我们的发现表明，先导化合物Gu1215是进一步临床前开发以克服多发性骨髓瘤中固有和获得性IMiD耐药性的有希望的候选者。
